Heterocycle substituted carboxylic acids

ABSTRACT

The present invention relates to compounds and pharmaceutically acceptable salts of formula (I):  
                 
which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia. Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-1B (PTP-1B), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application Ser.No. 60/467214, filed Apr. 30, 2003, which is incorporated herein byreference, in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to heterocyclic substituted carboxylic acids andmore specifically to such compounds that are useful in the treatment ofsyndrome X (consisting of such abnormalities as obesity, dyslipidemia,hypercoagulation, hypertension, insulin resistance and leading to heartdisease and diabetes), obesity, diabetes, immunological disease,bleeding disorders and/or cancer. More specifically, it relates to suchcompounds that are capable of inhibiting Protein tyrosine phosphatases(PTPs), in particular Protein tyrosine phosphatase-1B (PTP-1B) which isa negative regulator of the insulin and leptin signaling pathway andimproves insulin-sensitivity.

2. Description of the Related Art

This invention relates to a class of heterocycle substituted carboxylicacids that are inhibitors of various PTPs, in particular PTP-1B.

Protein tyrosine phosphatases are a large family of transmembrane orintracellular enzymes that dephosphorylate substrates involved in avariety of regulatory processes (Fischer et al., 1991, Science253:401-406). Protein tyrosine phosphatase-1B (PTP-1B) is anapproximately 50 kd intracellular protein, which is present in abundantamounts in various human tissues (Charbonneau et al., 1989, Proc. Natl.Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1-15).

Determining which proteins are substrates of PTP-1B has been ofconsiderable interest. One substrate which has aroused especial interestis the insulin receptor. The binding of insulin to its receptor resultsin autophosphorylation of the domain. This causes activation of theinsulin receptor tyrosine kinase, which phosphorylates the variousinsulin receptor substrate (IRS) proteins that propagate the insulinsignaling event further downstream to mediate insulin's variousbiological effects.

Seely et al., 1996, Diabetes 45:1379-1385 (“Seely”) studied therelationship of PTP-1B and the insulin receptor in vitro. Seelyconstructed a glutathione S-transferase (GST) fusion protein of PTP-1Bthat had a point mutation in the PTP-1B catalytic domain. Althoughcatalytically inactive, this fusion protein was able to bind to theinsulin receptor, as demonstrated by its ability to precipitate theinsulin receptor from purified receptor preparations and from whole celllysates derived from cells expressing the insulin receptor.

Ahmad et al., 1995, J. Biol. Chem. 270:20503-20508 used osmotic loadingto introduce PTP-1B neutralizing antibodies into rat KRC-7 hepatomacells. The presence of the antibody in the cells resulted in an increaseof 42% and 38%, respectively, in insulin stimulated DNA synthesis andphosphatidyinositol 3′ kinase activity. Insulin receptorautophosphorylation and insulin receptor substrate-1 tyrosinephosphorylation were increased 2.2 and 2.0-fold, respectively, in theantibody-loaded cells. The antibody-loaded cells also showed a 57%increase in insulin stimulated insulin receptor kinase activity towardexogenous peptide substrates.

Kennedy et al., 1999, Science 283: 1544-1548 showed that proteintyrosine phosphatase PTP-1B is a negative regulator of the insulinsignaling pathway, indicating that inhibitors of this enzyme arebeneficial in the treatment of Type 2 diabetes, which appears to involvea defect in an early process in insulin signal transduction rather thana structural defect in the insulin receptor itself. (J. M. Olefsky, W.T. Garvey, R. R. Henry, D. Brillon, S. Matthai and G. R. Freidenberg, G.R. (1988).) Cellular mechanisms of insulin resistance innon-insulin-dependent (Type II) diabetes. (Am. J. Med. 85: Suppl. 5A,86-105.) A drug that improved insulin sensitivity would have severaladvantages over traditional therapy of NIDDM using sulfonylureas, whichdo not alleviate insulin resistance but instead compensate by increasinginsulin secretion.

Ragab et al (2003, J. Biol. Chem 278(42), 40923-32) showed that PTP 1Bis involved in regulating platelet aggregation. Hence, inhibition of PTP1B can be predicted to have an effect on bleeding disorder, andcardiovascular disease.

Romsicki et al., (2003, Arch Biochem. Biophys 414(1), 40-50) showed thatTC PTP is structurally and functionally very similar. A PTP 1B inhibitoris very likely to also inhibit TC PTP. A knockout of the TC PTP geneproduces a phenotype with impaired immune function. (You-Ten et al.,1997, J. Exp. Med. 186(5), 683-93). Hence, inhibitors of PTP 1B can bepredict to inhibit TC PTP and modulate immune response.

It has also been demonstrated that PT-P1B is a negative regulator ofleptin signaling (Kaszua et al. Mol Cell. Endocrinology, 195:109-118,2002). PTP-1B deficient mice show enhanced potency for exogenous leptinto suppress food intake (Cheng, et al. Developmental Cell 2:497-503,2002). Thus, inhibitors of PTP-1B augment the beneficial effects ofleptin on food intake, body weight regulation and metabolism, in normalindividuals and leptin resistant individuals.

Therefore, inhibitors of PTPS, and inhibitors of PTP-1B in particular,are useful in controlling or treating obesity, syndrome X, Type 2diabetes, in improving glucose tolerance, and in improving insulinsensitivity in patients in need thereof. Such compounds are also usefulin treating or controlling other PTP mediated diseases, such as thetreatment of cancer, neurodegenerative diseases, immunologicaldisorders, bleeding and cardiovascular disorders, and the like.

SUMMARY OF THE INVENTION

In a broad aspect, the invention encompasses the compounds of formula(I) shown below, pharmaceutical compositions containing the compoundsand methods employing such compounds or compositions in the treatment ofdiabetes and/or cancer.

The invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein,

-   -   R₁ is H, C₁-C₆ alkyl, phenyl(C₁-C₆) alkyl, or C₃-C₆ alkenyl;    -   L is a bond, —SO₂—, —C(O)—, or —(C₁-C₄) alkyl-,    -   L₂ is a bond, —(C₁-C₄) alkyl-, —NR₈C(O)—, or —C(O)NR₈—;    -   L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)        alkyl-, alkenyl, or C(O);    -   R₂ is arylalkoxy, aryl, arylalkyl, alkoxycarbonyl, C₁-C₆ alkyl,        C₁-C₆ alkoxy, —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄)        alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄) alkyl-C(O)N(C₁-C₄)        alkyl(C₁-C₄)alkyl, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl,        —SO₂-aryl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄)        alkyl-heterocycloalkyl, or OH,        -   wherein each heterocycloalkyl is optionally substituted with            a total of 1, 2, 3, or 4 groups that are independently            halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or —SO₂—(C₁-C₄) alkyl;        -   wherein each aryl group within R₂ is optionally substituted            with 1, 2, 3, 4, or 5 groups that are independently alkyl,            alkoxy, halogen, haloalkyl, haloalkoxy, or NO₂;        -   wherein b is 0, 1, or 2;        -   each R₆ and R₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)            alkyl, alkanoyl, arylalkanoyl, alkoxycarbonyl,            arylalkoxycarbonyl, heteroarylcarbonyl, heteroaryl,            heterocycloalkylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,            —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-aryl, wherein the            cyclic groups are optionally substituted with 1, 2, 3, or 4            groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄            alkoxy, NO₂, OH, NH₂, NH(C₁-C₆) alkyl,            N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or haloalkoxy;        -   R₈ is H or C₁-C₆ alkyl;    -   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H,        arylalkoxy, arylalkyl, halogen, alkyl, OH, alkoxy, NO₂, NH₂,        NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-aryl,        NHC(O)—(C₁-C₄) alkyl-aryl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄)alkyl-aryl,        N(C₁-C₄)alkyl-aryl, —NHSO₂-aryl, —N(C₁-C₄alkyl)SO₂aryl, wherein        the aryl group is optionally substituted with 1, 2, 3, or 4        groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,        halogen, OH, NO₂, haloalkyl, haloalkoxy;    -   the A ring is aryl, heteroaryl, or heterocycloalkyl, each of        which is optionally substituted with 1, 2, or 3 groups that are        independently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, haloalkyl,        haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl (C₁-C₆)        alkyl;    -   the B ring is heterocycloalkyl, or heteroaryl, wherein each is        optionally substituted with 1, 2, 3, or 4 groups that are        independently alkyl, alkoxy, arylalkyl, arylalkoxy, halogen,        alkoxycarbonyl, aryl, or OH;    -   Q is H, aryl, -aryl-carbonyl-aryl, -aryl-alkyl-aryl,        -aryl-alkyl-heteroaryl, -aryl-heteroaryl, -heteroaryl-aryl,        -aryl-heterocycloalkyl, heteroaryl, -heteroaryl-alkyl-aryl, or        -heterocycloalkyl, wherein the aforementioned cyclic groups are        optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,        halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl;    -   Y is selected from a bond, —NHC(O)—(C₁-C₄)alkyl-,        —N(C₁-C₄)alkyl-C(O)—(C₁-C₄)alkyl-, —(C₁-C₄)alkyl- wherein the        alkyl is optionally substituted with phenyl, or —NHC(O)—; and    -   Z is absent or phenyl optionally substituted with 1, 2, 3, or 4        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, or hydroxy.

The compounds of formula I bind to PTPs, and in particular to PTP-1B.The interaction with the enzyme, specifically PTP-1B, preferably resultsin inhibition of the enzyme.

The invention also includes intermediates that are useful in making thecompounds of the invention.

The invention also provides pharmaceutical compositions comprising acompound or salt of formula I and at least one pharmaceuticallyacceptable carrier, solvent, adjuvant or diluent.

The invention further provides methods of treating disease such asdiabetes, syndrome X, cancer, immunological disease, bleeding disorders,or cardiovascular disease in a patient in need of such treatment,comprising administering to the patient a compound or pharmaceuticallyacceptable salt of formula I, or a pharmaceutical composition comprisinga compound or salt of formula I.

In another aspect, the invention provides a method for inhibitingprotein tyrosine phosphatases, preferably PTP-1B, comprisingadministering a therapeutically effective amount of a compound offormula I.

In another aspect, the invention provides a method for treatingmetabolic disorders related to insulin resistance or hyperglycemia,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound of formula I.

The invention also provides the use of a compound or salt according toformula I for the manufacture of a medicament for use in treatingdiabetes or cancer or other diseases related to PTP.

The invention also provides methods of preparing the compounds of theinvention and the intermediates used in those methods.

The invention also provides methods and compositions for combinationtherapy of Type I and Type II diabetes. In these embodiments, theinvention provides formulations and pharmaceutical compositions, as wellas methods for treating Type I and Type II diabetes with the compoundsof formula I plus additional compounds and medicaments as disclosed inmore detail below. In these embodiments, the methods of the inventioncan comprise treatment methods for Type I and Type II diabetes where thecompounds of formula I are formulated with a therapeutically-effectiveamount of said additional compounds and medicaments. In alternativeembodiments, treatment methods of the invention for Type I and Type IIdiabetes comprise administration of the inventive compounds of formula Ias disclosed herein concomitantly, simultaneously or together with atherapeutically-effective amount of said additional compounds andmedicaments.

DETAILED DESCRIPTION OF THE INVENTION

A preferred class of compounds of formula I are compounds of formulaI-a, wherein

-   -   R₁ is H, C₁-C₆ alkyl, benzyl, or allyl;    -   L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)        alkyl-, or C(O);    -   R₂ is phenyl C₁-C₄ alkoxy, phenyl, naphthyl, phenyl C₁-C₄ alkyl,        naphthyl C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl , C₁-C₆ alkyl, C₁-C₆        alkoxy, —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄)        alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄)        alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, —(C₁-C₄)        alkyl-S(O)_(b)—(C₁-C₄) alkyl, —SO₂-phenyl, —SO₂-naphthyl,        (C₁-C₄) hydroxyalkyl, —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄)        alkyl-pyrrolidinyl, —(C₁-C₄) alkyl-morpholinyl, or OH,        -   wherein the piperidinyl, pyrrolidinyl and morpholinyl rings            are optionally substituted with 1, 2, 3, or 4 groups that            are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or            —SO₂—(C₁-C₄) alkyl;        -   wherein the phenyl and naphthyl groups are optionally            substituted with 1, 2, 3, 4, or 5 groups that are            independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄            haloalkyl, C₁-C₄ haloalkoxy, or NO₂;        -   wherein b is 0, 1, or 2;        -   R₈ is H or C₁-C₆ alkyl;    -   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H, phenyl        C₁-C₆ alkoxy, phenyl C₁-C₆ alkyl, halogen, C₁-C₆ alkyl, OH,        C₁-C₆ alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl,        N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl, NHC(O)—(C₁-C₄)        alkyl-phenyl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄) alkyl-phenyl,        N(C₁-C₄)alkyl-phenyl, —NHSO₂-phenyl, —N(C₁-C₄alkyl)SO₂phenyl,        wherein the phenyl group is optionally substituted with 1, 2, 3,        or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,        halogen, OH, NO₂, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy;    -   the A ring is phenyl, indolyl, benzofuranyl, dibenzofuranyl,        thiazolyl, or isoindolyl, each of which is optionally        substituted with 1, 2, or 3 groups that are independently,        halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, haloalkyl, haloalkoxy, NO₂,        NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl (C₁-C₆) alkyl;    -   the B ring is pyrrolidinyl, tetrahydroisoquinolinyl,        piperidinyl, piperazinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl,        thiazolidinyl, dihydroquinoxalinonyl, pyridinonyl,        dihydroisoquinolinyl, indolyl, benzimidazolyl, quinolinyl,        pyridinyl, or pyrimidinyl, wherein each is optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl (C₁-C₄) alkoxy        (benzyloxy), halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH;    -   Q is H, phenyl, -phenyl-carbonyl-phenyl, -phenyl-alkyl-phenyl,        -phenyl-alkyl-benzofuranyl, -phenyl-pyridyl,        -phenyl-benzofuranyl, -phenyl-piperidinyl, -phenyl-pyrrolidinyl,        indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl,        -pyridyl-phenyl, -pyrimidyl-phenyl, -benzofuranyl-C₁-C₄        alkyl-phenyl, -pyridyl-C₁-C₄ alkyl-phenyl, -piperidinyl,        pyrrolidinyl, or indolinyl, wherein each aforementioned cyclic        group is optionally substituted with 1, 2, 3, 4, or 5 groups        that are independently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NR₆R₇, or        phenyl;    -   Y is selected from a bond, —NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄)        alkylC(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl- wherein the alkyl is        optionally substituted with phenyl, or —NHC(O)—; and    -   Z is absent or phenyl optionally substituted with 1, 2, 3, or 4        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, or hydroxy.

Preferred compounds of formula I-a are compounds of formula I-b, wherein

-   -   R₂₂ and R₂₃ are both H;    -   R₂ is benzyloxy, phenethyloxy, phenyl, phenyl C₁-C₄ alkyl,        —CH₂-naphthyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,        —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄) alkyl-C(O)NH(C₁-C₄)alkyl,        —(C₁-C₄) alkyl-C(O)N(C₁-C₄) alkyl (C₁-C₄) alkyl, —(C₁-C₄)        alkyl-S(O)_(b)—(C₁-C₄) alkyl, —SO₂-phenyl, (C₁-C₄) hydroxyalkyl,        —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄) alkyl-pyrrolidinyl,        —(C₁-C₄) alkyl-morpholinyl, or OH,        -   wherein the piperidinyl, pyrrolidinyl and morpholinyl groups            are optionally substituted with 1, 2, or 3 groups that are            independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or            —SO₂—(C₁-C₄) alkyl;        -   wherein the phenyl and naphthyl groups are optionally            substituted with 1, 2, 3, 4, or 5 groups that are            independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄            haloalkyl, C₁-C₄ haloalkoxy, or NO₂;    -   each R₆ and R₇ are independently H, C₁-C₆ alkyl,        phenyl(C₁-C₆)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₆)alkanoyl,        (C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₆)alkoxycarbonyl,        pyridylcarbonyl, pyridyl, piperidinyl, morpholinyl,        pyrrolidinylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,        —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-phenyl, wherein the        cyclic groups are optionally substituted with 1, 2, 3, or 4        groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,        C₁-C₄ haloalkyl or C₁-C₄ haloalkoxy;        -   wherein b is 0, 1, or 2; and    -   Z is absent.

Preferred compounds of formula I-b include compounds of formula II,which has the formula

wherein

-   -   n is 0, 1, 2, 3, or 4;    -   each R₁₀ is independently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,        haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)        alkyl (C₁-C₆) alkyl;    -   the B ring is pyrrolidinyl, tetrahydroisoquinolinyl,        piperidinyl, piperazinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl,        thiazolidinyl, dihydroquinoxalinonyl, pyridinonyl, or        dihydroisoquinolinyl, wherein each is optionally substituted        with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy,        phenyl (C₁-C₄) alkyl (benzyl), phenyl (C₁-C₄) alkoxy        (benzyloxy), halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH;    -   Q is H, phenyl, -phenyl-carbonyl-phenyl, -phenyl-alkyl-phenyl,        -phenyl-pyridyl, -phenyl-benzofuranyl, -phenyl-piperidinyl,        -phenyl-pyrrolidinyl, indolizinyl, benzofuranyl, indolyl,        isoindolyl, quinolinyl, -benzofuranyl-C₁-C₄ alkyl-phenyl,        -pyridyl-C₁-C₄ alkyl-phenyl, -piperidinyl, -pyrrolidinyl,        -indolinyl, wherein the aforementioned cyclic groups are        optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,        halogen, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NR₆R₇, or phenyl;        wherein        -   each R₆ and R₇ are independently H, C₁-C₆ alkyl,            phenyl(C₁-C₄)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl,            (C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl,            pyridylcarbonyl, or —SO₂-phenyl, wherein the cyclic groups            are optionally substituted with 1, 2, 3, or 4 groups that            are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂,            OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄            haloalkyl or C₁-C₄ haloalkoxy; and    -   Y is selected from a bond, —NHC(O)—(C₁-C₄)alkyl-, —N(C₁-C₄)        alkylC(O)—(C₁-C₄)alkyl-, —(C₁-C₄)alkyl- wherein the alkyl is        optionally substituted with phenyl, or —NHC(O)—.

Preferred compounds of formula II include compounds of formula II-a,wherein

-   -   L is a bond or —(C₁-C₄) alkyl-.

Preferred compounds of formula II include compounds of formula II-b,wherein

-   -   L is —SO₂— or —C(O)—.

Preferred compounds of formulas II, II-a, or II-b, include compounds offormula II-c, wherein

-   -   L₃ is a bond or —(C₁-C₄) alkyl-.

Preferred compounds of formulas II, II-a, or II-b, include compounds offormula II-d, wherein

-   -   L₃ is —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, or C(O). In another        preferred embodiment, L₃ is C(O).

Preferred compounds of formulas II, include compounds of formula II-e,wherein

-   -   R₁ is H or C₁-C₄ alkyl; and    -   R₂ is benzyloxy, phenethyloxy, phenyl, phenyl C₁-C₄ alkyl,        —CH₂-naphthyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,        —(C₁-C₄) alkyl-S(O)₂—(C₁-C₄) alkyl, —SO₂-phenyl, (C₁-C₄)        hydroxyalkyl, —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄)        alkyl-pyrrolidinyl, —(C₁-C₄) alkyl-morpholinyl, or OH, wherein        the piperidinyl, pyrrolidinyl and morpholinyl groups are        optionally substituted with a total of 1, 2, or 3 groups that        are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or        —SO₂—(C₁-C₄) alkyl;        -   wherein the phenyl and naphthyl groups are optionally            substituted with 1, 2, 3, 4, or 5 groups that are            independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄            haloalkyl, C₁-C₄ haloalkoxy, or NO₂.

Preferred compounds of formulas II-e, include compounds of formula II-f,wherein

-   -   R₂₀, and R₂₁ are independently selected from H, benzyloxy,        benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂,        NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl,        N(C₁-C₄)alkyl-phenyl, wherein the phenyl group is optionally        substituted with 1, 2, 3, or 4 groups that are independently        C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl,        C₁-C₄ haloalkoxy; and    -   the B ring is pyrrolidinyl, tetrahydroisoquinolinyl,        piperidinyl, pyrrolidinonyl, thiazolidinyl, pyrrolyl, pyrazolyl,        dihydroquinoxalinonyl, pyridinonyl, wherein each is optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, benzyl, benzyloxy, halogen, C₁-C₆ alkoxycarbonyl,        phenyl, OH.

Preferred compounds of formulas II-f, include compounds of formula II-g,wherein

-   -   Q is H, phenyl, -phenyl-carbonyl-phenyl, -phenyl-C₁-C₂        alkyl-phenyl, -phenyl-pyridyl, -phenyl-benzofuranyl,        indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl,        -benzofuranyl-C₁-C₄ alkyl-phenyl, -pyridyl-C₁-C₄ alkyl-phenyl,        -piperidinyl, -pyrrolidinyl, or -indolinyl, wherein the        aforementioned cyclic groups are optionally substituted with 1,        2, 3, 4, or 5 groups that are independently C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃,        NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, benzyl, C₂-C₆        alkanoyl, phenyl(C₁-C₄)alkanoyl, (C₁-C₆)alkoxycarbonyl,        phenyl(C₁-C₄)alkoxycarbonyl, or —SO₂-phenyl, wherein the cyclic        groups are optionally substituted with 1, 2, 3, or 4 groups that        are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH,        NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄ haloalkyl        or C₁-C₄ haloalkoxy.

Preferred compounds of formulas II-g, include compounds of formula II-h,wherein

-   -   R, is H.

Preferred compounds of formulas II-g or II-h include compounds offormula II-i, wherein

-   -   Q is H, phenyl, indolizinyl, benzofuranyl, indolyl,        -benzofuranyl-C₁-C₄ alkyl-phenyl, or -indolinyl, wherein the        aforementioned cyclic groups are optionally substituted with 1,        2, 3, 4, or 5 groups that are independently C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen.

Preferred compounds of formulas II-i, include compounds of formula II-j,wherein

-   -   R₂₀ and R₂, are independently selected from H, benzyloxy,        benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂,        NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.

Preferred compounds of formula II-g include compounds of formula III,wherein

wherein

-   -   n is 0, 1, 2, 3, or 4;    -   each R₁₀ is independently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,        haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or        N(C₁-C₆)alkyl (C₁-C₆)alkyl;    -   L₃ is a bond, or —(C₁-C₄) alkyl-;    -   R₁ is H or C₁-C₄ alkyl;    -   R₂ is benzyloxy, phenyl, phenyl C₁-C₄ alkyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —SO₂-phenyl, (C₁-C₄)        hydroxyalkyl or OH,        -   wherein the phenyl group is optionally substituted with 1,            2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,            C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or            NO₂.    -   R₂₀, and R₂₁ are independently selected from H, benzyloxy,        benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, and NO₂;    -   the B ring is pyrrolidinyl, tetrahydroisoquinolinyl,        piperidinyl, pyrrolidinonyl, thiazolidinyl, pyrrolyl, pyrazolyl,        dihydroquinoxalinonyl, pyridinonyl, wherein each is optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, benzyl, benzyloxy, halogen, C₁-C₆ alkoxycarbonyl,        phenyl, or OH;    -   Q is H, phenyl, indolizinyl, benzofuranyl, indolyl, isoindolyl,        quinolinyl, or -benzofuranyl-CH₂-phenyl, wherein the        aforementioned-cyclic groups are optionally substituted with 1,        2, 3, 4, or 5 groups that are independently C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃,        NR₆R₇, or phenyl; wherein        -   R₆ and R₇ are independently H, C₁-C₆ alkyl, benzyl, C₂-C₆            alkanoyl, phenyl(C₁-C₄)alkanoyl, or —SO₂-phenyl, wherein the            phenyl groups are optionally substituted with 1, 2, 3, or 4            groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄            alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,            N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

Preferred compound of formula III include compounds of formula III-a,wherein

-   -   Y is a bond or —(C₁-C₄) alkyl-.

Preferred compound of formula III include compounds of formula III-b,wherein

-   -   Y is selected from —NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄) alkyl        C(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl- wherein the alkyl is        optionally substituted with phenyl, or —NHC(O)—.

Preferred compounds of formulas III-a or III-b include compounds offormula III-c, wherein

-   -   -L₃-Q is attached to the phenyl ring as shown:

Preferred compound of formula III-c include compounds of formula III-d,wherein

-   -   L is a bond or —(C₁-C₄) alkyl-.

Preferred compound of formula III-c include compounds of formula III-e,wherein

-   -   L is —SO₂— or —C(O)—.

Preferred compounds of formula III, III-a, III-b, III-c, III-d, or III-einclude compounds of formula III-f, wherein n is 0 or 1, more preferably0.

Preferred compounds of formula I include compounds of formula IV,wherein

wherein

-   -   n is 0, 1, 2, 3, or 4;    -   each R₁₀ is independently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,        haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)        alkyl (C₁-C₆) alkyl;    -   R₁ is H, C₁-C₄ alkyl, benzyl or allyl;    -   the B ring is indolyl, benzimidazolyl, quinolinyl, pyrrolyl,        pyrazolyl, pyrimidinyl, or pyridinyl, wherein each is optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl (C₁-C₄) alkoxy        (benzyloxy), halogen, C₁-C₆ alkoxycarbonyl, phenyl, OH.

Preferred compounds of formula IV include compounds of formula IV-a,wherein

-   -   Q is H, phenyl, -phenyl-benzyl, -phenyl-pyridyl,        -phenyl-benzofuranyl, -phenyl-C₁-C₄ alkyl-benzofuranyl,        -phenyl-piperidinyl, -phenyl-pyrrolidinyl, indolizinyl,        benzofuranyl, indolyl, isoindolyl, quinolinyl,        -benzofuranyl-C₁-C₄ alkyl-phenyl, -pyridyl-C₁-C₄ alkyl-phenyl,        -piperidinyl, pyrrolidinyl, or indolinyl, wherein the        aforementioned cyclic groups are optionally substituted with 1,        2, 3, 4, or 5 groups that are independently C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₂        haloalkyl, C₁-C₂ haloalkoxy, NR₆R₇, or phenyl; wherein        -   R₆ and R₇ are independently H, C₁-C₆ alkyl,            phenyl(C₁-C₄)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl,            (C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₄) alkoxycarbonyl,            pyridylcarbonyl, or —SO₂-phenyl, wherein the cyclic groups            are optionally substituted with 1, 2, 3, or 4 groups that            are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂,            OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄            haloalkyl or C₁-C₄ haloalkoxy.

Preferred compounds of formula IV-a include compounds of formula IV-b,wherein

-   -   R₁ is H, or C₁-C₄ alkyl;    -   R₂ is benzyloxy, phenyl, phenyl C₁-C₄ alkyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —SO₂-phenyl, (C₁-C₄)        hydroxyalkyl or OH,        -   wherein the aryl group is optionally substituted with 1, 2,            3, 4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆            alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or NO₂;            and    -   R₂₀, and R₂₁ are independently selected from H, benzyloxy,        benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, and NO₂.

Preferred compounds of formula IV-b include compounds of formula IV-c,wherein

-   -   L is a bond or —(C₁-C₄) alkyl-.

Preferred compounds of formula IV-b include compounds of formula IV-d,wherein

-   -   L is —SO₂— or —C(O)—.

Preferred compounds of formulas IV-c or IV-d include compounds offormula IV-e, wherein

-   -   L₃ is a bond, —(C₁-C₄) alkyl-, or C(O). In a more preferred        aspect, L₃ is a bond, or —(C₁-C₄) alkyl-.

Preferred compounds of formulas IV-c or IV-d include compounds offormula IV-f, wherein

-   -   L₃ is —(C₁-C₄)alkyl-O—, or —O—(C₁-C₄)alkyl. In a more preferred        aspect, L₃ is —(C₁-C₄)alkyl-O—.

Preferred compounds of formula IV-b include compounds of formula IV-g,wherein

-   -   the B ring is indolyl, benzimidazolyl, or pyridinyl, wherein        each is optionally substituted with 1, 2, 3, or 4 groups that        are independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl        (C₁-C₄) alkoxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH;        and    -   Y is selected from a bond, —NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄)        alkylC(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl-phenyl, or —NHC (O)—.

Preferred compounds of formula IV-g include compounds of formula IV-h,wherein

-   -   the B ring is pyrrolyl, or pyrazolyl, wherein each is optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, phenyl(C₁-C₄) alkyl, benzyloxy, halogen, C₁-C₆        alkoxycarbonyl, phenyl, or OH.

Preferred compounds of formula IV-g include compounds of formula IV-i,wherein

-   -   L₃ is a bond, or -C₁-C₄ alkyl-,    -   the A-ring is benzofuranyl, indolyl, isoindolyl, dibenzofuranyl,        or thiazolyl, each of which is optionally substituted with 1, 2,        or 3 groups that are independently, halogen, C₁-C₆ alkyl, C₁-C₄        alkoxy, haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or        N(C₁-C₆) alkyl (C₁-C₆) alkyl;    -   Q is phenyl, indolizinyl, benzofuranyl, indolyl, isoindolyl,        quinolinyl, -benzofuranyl-C₁-C₄ alkyl-phenyl, wherein the        aforementioned cyclic groups are optionally substituted with 1,        2, 3, 4, or 5 groups that are independently C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₂        haloalkyl, C₁-C₂ haloalkoxy, NR₆R₇, or phenyl; wherein        -   R₆ and R₇ are independently H, C₁-C₆ alkyl,            phenyl(C₁-C₄)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl,            (C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl, or            —SO₂-phenyl, wherein the cyclic groups are optionally            substituted with 1, 2, 3, or 4 groups that are independently            halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,            NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄ haloalkyl            or C₁-C₄ haloalkoxy.

Preferred compounds of formula IV-i include compounds of formula IV-j,wherein

-   -   R₂ is benzyloxy, phenyl, phenyl C₁-C₄ alkyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —SO₂-phenyl, (C₁-C₄)        hydroxyalkyl or OH,        -   wherein the aryl group is optionally substituted with 1, 2,            3, 4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆            alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or NO₂;    -   the B ring is indolyl, benzimidazolyl, pyridinyl, pyrrolidinyl,        pyridinonyl, quinoxalinonyl, pyrrolyl, pyrazolyl benzimidazolyl,        quinoxalinyl, wherein each is optionally substituted with 1, 2,        3, or 4 groups that are independently alkyl, alkoxy, phenyl        (C₁-C₄) alkyl, phenyl (C₁-C₄) alkoxy (benzyloxy), halogen, C₁-C₆        alkoxycarbonyl, phenyl, or OH;    -   R₂₀, and R₂₁ are independently selected from H, benzyloxy,        benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, and NO₂, and    -   R₂₂ and R₂₃ are both H.

Preferred compounds of formula IV-j include compounds of formula IV-k,wherein

-   -   L₃ is a bond, or —C₁-C₄ alkyl-,    -   the A-ring is benzofuranyl, indolyl, isoindolyl, dibenzofuranyl,        thiazolyl, each of which is optionally substituted with 1, 2, or        3 groups that are independently, halogen, C₁-C₆ alkyl, C₁-C₄        alkoxy, haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or        N(C₁-C₆) alkyl (C₁-C₆) alkyl;    -   Q is phenyl, indolizinyl, benzofuranyl, indolyl,        -benzofuranyl-C₁-C₄ alkyl-phenyl, wherein the aforementioned        cyclic groups are optionally substituted with 1, 2, 3, 4, or 5        groups that are independently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl,        C₁-C₆ alkoxy, halogen, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NR₆R₇,        or phenyl; wherein        -   R₆ and R₇ are independently H, C₁-C₆ alkyl, benzyl, C₂-C₆            alkanoyl, phenyl(C₁-C₂)alkanoyl, or —SO₂-phenyl, wherein the            phenyl groups are optionally substituted with 1, 2, 3, or 4            groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄            alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,            N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃, or OCF₃;    -   Z is absent or phenyl optionally substituted with 1, 2, 3, or 4        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, or hydroxy; R, is H or C₁-C₆ alkyl;    -   R₂ is benzyloxy, phenyl, phenyl C₁-C₄ alkyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —SO₂-phenyl, (C₁-C₄)        hydroxyalkyl or OH,        -   wherein the phenyl group is optionally substituted with 1,            2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,            C₁-C₆ alkoxy, halogen, CF₃, OCF₃, or NO₂;    -   the B ring is indolyl, benzimidazolyl, pyridinyl, pyrrolidinyl,        pyridinonyl, quinoxalinonyl, pyrazolyl, pyrrolyl,        benzimidazolyl, quinoxalinyl, wherein each is optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl (C₁-C₄) alkoxy,        halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH;    -   R₂₀, and R₂₁ are independently selected from H, benzyloxy,        benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, and NO₂, and    -   R₂₂ and R₂₃ are both H.

Preferred compounds of formula IV-k include compounds of formula IV-l,wherein

-   -   the A-ring is benzofuranyl, indolyl, or dibenzofuranyl, each of        which is optionally substituted with 1, 2, or 3 groups that are        independently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, haloalkyl,        haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl (C₁-C₆)        alkyl.

Preferred compounds of formula IV-l include compounds of formula IV-m,wherein

-   -   the B ring is indolyl, benzimidazolyl, pyridinyl, pyrrolidinyl,        pyridinonyl, pyrazolyl, pyrrolyl, or benzimidazolyl, wherein        each is optionally substituted with 1, 2, 3, or 4 groups that        are independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl        (C₁-C₄) alkoxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH;        and Z is absent.

Preferred compounds of formula IV-m include compounds of formula IV-n,wherein

-   -   the B ring is pyrazolyl, indolyl, or benzimidazolyl, each of        which is optionally substituted with 1, 2, 3, or 4 groups that        are independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl        (C₁-C₄) alkoxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH.

Preferred compounds of formula IV-k include compounds of formula V,wherein

wherein

-   -   L₂ is a bond or —(C₁-C₂) alkyl-; (preferably a bond or —CH₂—)    -   R₁ is H or C₁-C₆ alkyl, preferably H;    -   R₁₀ is halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, haloalkyl,        haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or        N(C₁-C₆)alkyl(C₁-C₆)alkyl; or    -   R₁₀ is -L₃-Q.

Preferred compounds of formula V include compounds of formula V-a,wherein

-   -   R₁₀ is C₁-C₆ alkyl.

Preferred compounds of formula V include compounds of formula V-b,wherein

-   -   R₁₀ is -L₃-Q, wherein        -   L₃ is —CH₂—; and        -   Q is phenyl.

Preferred compounds of formula IV-k include compounds of formula VI,

Preferred compounds of formula VI include compounds of formula VI-a,wherein

-   -   R, is H or C₁-C₆ alkyl; and    -   Y is a bond or C₁-C₄ alkyl.

Preferred compounds of formula VI-a include compounds of formula VI-b,wherein

-   -   L₃ is a bond; and    -   Q is hydrogen.

Preferred compounds of any one of formulas V, V-a, V-b, VI, VI-a or VI-binclude compounds of formula VI-c, wherein

-   -   the B ring is indolyl, benzimidazolyl, pyridinyl, pyrrolidinyl,        pyridinonyl, quinoxalinonyl, or benzimidazolyl, wherein each is        optionally substituted with 1, 2, 3, or 4 groups that are        independently alkyl, alkoxy, benzyl, phenethyl, benzyloxy,        halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH.

Preferred compounds of formula VI-c, include compounds of formula VI-d,wherein

-   -   L is a bond or —(C₁-C₄) alkyl-.

Preferred compounds of formula VI-c, include compounds of formula VI-e,wherein

-   -   L is SO₂, or —C(O)—.

Preferred compounds of formulas VI-c or VI-d include compounds offormula VI-f, wherein

-   -   L₂ is a bond.

Preferred compounds of formulas VI-c or VI-d include compounds offormula VI-g, wherein

-   -   L₂ is —NHC(O)—.

Preferred compounds of formulas VI-c or VI-d include compounds offormula VI-h, wherein

-   -   L₂ is —N(C₁-C₄)alkyl-C(O)—.

Other preferred compounds of formula IV-k include compounds of formulaIV-o, wherein

-   -   R₁ is H or C₁-C₆ alkyl;    -   Z is phenyl optionally substituted with 1, 2, 3, or 4 groups        that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or        hydroxy.

Preferred compounds of formula IV-o include compounds of formula IV-p,wherein

-   -   the A-ring is benzofuranyl, indolyl, or dibenzofuranyl,        thiazolyl. More preferably, the A-ring is thiazolyl.

Preferred compounds of formula IV-k include compounds of formula IV-q,wherein

-   -   R₁ is H; and    -   the A-ring is dibenzofuranyl.

Preferred compounds of formula IV-q include compounds of formula IV-r,wherein

-   -   Z is absent.

Preferred compounds of any one of formulas V, V-a, V-b, VI, VI-a, VI-b,VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, IV-o, IV-p, IV-q, include compoundsof formula IV-s, wherein

-   -   the B ring is indolyl, or benzimidazolyl, each is optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, benzyl, phenethyl, phenpropyl, benzyloxy,        halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH.

Preferred compounds of any one of formulas V, V-a, V-b, VI, VI-a, VI-b,VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, IV-o, IV-p, IV-q, include compoundsof formula IV-t, wherein

-   -   the B ring is pyridinyl, pyrrolidinyl, or pyridinonyl, wherein        each is optionally substituted with 1, 2, 3, or 4 groups that        are independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl        (C₁-C₄) alkoxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH.

Preferred compounds of any one of formulas V, V-a, V-b, VI, VI-a, VI-b,VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, IV-o, IV-p, IV-q, include compoundsof formula IV-u, wherein

-   -   the B ring is benzimidazolyl or quinoxalinyl, wherein each is        optionally substituted with 1, 2, 3, or 4 groups that are        independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl        (C₁-C₄) alkoxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH.        More preferably, the B ring is benzimidazolyl optionally        substituted with 1, 2, 3, or 4 groups that are independently        alkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl (C₁-C₄) alkoxy,        halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH.

Preferred compounds formula IV-k include compounds of the formula IV-s,wherein

wherein

-   -   R₁ is H or C₁-C₄ alkyl;    -   R₁₀ is halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, haloalkyl,        haloalkoxy, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl;        or    -   R₁₀ is -L₃-Q;    -   R₂ is benzyloxy, phenyl, phenyl C₁-C₄ alkyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, —SO₂-phenyl, or OH, wherein the        phenyl group is optionally substituted with 1, 2, 3, 4, or 5        groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,        halogen, CF₃, OCF₃, or NO₂; and    -   Y is C₁-C₄ alkyl.

In another aspect, the invention provides A method of treating type 1 ortype 2 diabetes comprising administering a pharmaceutically acceptableamount of a compound of formula I to a patient in need thereof.Preferably the patient is a human.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound according to formula I and at least onepharmaceutically acceptable solvent, carrier, excipient or adjuvant.

In another aspect, the invention provides a method of treating diabetes,comprising administering to a patient in need of such treatment apharmaceutically acceptable amount of a compounds of formula I.

In another aspect, the invention encompasses a method of treatingdiabetes comprising administering to a patient in need thereof, apharmaceutically acceptable amount of a compound or salt of formula I ora pharmaceutical composition comprising a compound or salt of formula I.

In another aspect, the invention encompasses a method of inhibitingTPT-1B comprising administering to a patient in need thereof, apharmaceutically acceptable amount of a compound or salt of formula I ora pharmaceutical composition comprising a compound or salt of formula I.

In another aspect, the invention encompasses a method of treating canceror neurodegenerative diseases comprising administering to a patient inneed thereof, a pharmaceutically acceptable amount of a compound or saltof formula I or a pharmaceutical composition comprising a compound orsalt of formula I.

Illustrative compounds of the invention include the following, whichwere named using ChemDraw v. 6.02, which is sold by Cambridgesoft.com inCambridge, Mass., or using Name Pro IUPAC Naming Software, version 5.09,available from Advanced Chemical Development, Inc., 90 Adelaide StreetWest, Toronto, Ontario, M5H 3V9, Canada. 1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4- (benzyloxy)proline

{1-benzyl-5-[4-(1H-indol-1- yl)phenyl]-1H-indol-3-yl}acetic acid

[5-[4-(1H-indol-1-yl)phenyl]-1- (2-naphthylmethyl)-1H-indol-3- yl]aceticacid

4-{2-benzyl-5-[4-(2-benzyl-1- benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}butonic acid

(1-benzyl-5-(4- dibenzo[b,d]furan-4-ylphenyl)-2-oxo-1,2-dihydropyridin-3- yl]amino}(oxo)acetic acid

As noted above, the compounds of the invention bind to and preferablyinhibit PTP-1B. As a result these compounds are useful in the treatmentof various diseases, including controlling or treating Type 2 diabetes,improving glucose tolerance, and in improving insulin sensitivity inpatients in need thereof. The compounds are also useful in treating orcontrolling other PTP-1B mediated diseases, such as the treatment ofcancer, neurodegenerative diseases and the like.

The term “alkoxy” represents an alkyl group of indicated number ofcarbon atoms attached to the parent molecular moiety through an oxygenbridge. Examples of alkoxy groups include, for example, methoxy, ethoxy,propoxy and isopropoxy.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight, orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examplesof aryl groups include phenyl, naphthyl, and anthracenyl. More preferredaryl groups are phenyl and naphthyl. Most preferred is phenyl.

The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, andiodine.

The term “heterocycloalkyl,” refers to a ring or ring system containingat least one heteroatom selected from nitrogen, oxygen, and sulfur,wherein said heteroatom is in a non-aromatic ring. The heterocycloalkylring is optionally fused to or otherwise attached to otherheterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/orphenyl rings. Preferred heterocycloalkyl groups have from 3 to 7members. Examples of heterocycloalkyl groups include, for example,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl,tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl.Preferred heterocycloalkyl groups include piperidinyl, piperazinyl,morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, andpyrrolidinonyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen, and sulfur. Theheteroaryl ring may be fused or otherwise attached to one or moreheteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thienyl, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl,benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl,triazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

When the either or both the A and B rings are substituted, thesubstitution may occur on either a carbon or on a heteroatom.

The compounds of this invention may contain one or more asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless otherwise specified, itis intended that the compounds include the cis, trans, Z- and E-configurations. Likewise, all tautomeric forms are also intended to beincluded.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;-dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical gel, spray,ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In the case of skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.Preferred non-human animals include domesticated animals.

As noted above, the invention also provides methods and compositions forcombination therapy of Type I and Type II diabetes. In one such aspect,the invention provides methods of using compounds of formula I incombination with one or more angiotensin converting enzyme (ACE)inhibitors for improving the cardiovascular risk profile in patientsexperiencing or subject to Syndrome X or type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics. These methods may also be characterized as the reduction ofrisk factors for heart disease, stroke or heart attack in a type IIdiabetic.

These methods include the reduction of hyperlipidemia in a patientsexperiencing or subject to Syndrome X or type II diabetes. These methodsinclude methods lowering low density lipoprotein (LDL) blood levels andto increase high density lipoprotein (HDL) blood levels. The methodsherein may further be characterized as useful for inhibiting, preventingor reducing atherosclerosis in a type II diabetics, or for reducing therisk factors thereof.

These methods also include the lowering of free fatty acid blood levelsand triglyceride levels in type II diabetics.

Among the ACE inhibitors which may be utilized with the inventiondescribed herein are quinapril, ramipril, verapamil, captopril,diltiazem, clonidine, hydrochlorthiazide, benazepril, prazosin,fosinopril, lisinopril, atenolol, enalapril, perindropril, perindropriltert-butylamine, trandolapril and moexipril, or a pharmaceuticallyacceptable salt form of one or more of these compounds.

The invention also provides methods of using PTPase inhibitors offormula I for improving the cardiovascular or cerebrovascular riskprofile in patients experiencing or subject to type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics or a patient experiencing or subject to Syndrome X. Thesemethods may also be characterized as the reduction of risk factors forheart disease, stroke or heart attack in a type II diabetic or a patientexperiencing or subject to Syndrome X.

The invention also provides methods of using a pharmacologicalcombination of one or more PTPase inhibiting agents, one or morebiguanide agents, and, optionally one or more sulfonlylurea agents fortreatment of type II diabetes or Syndrome X in a patient in need of suchtreatment. Also provided are methods of using these agents to treat orinhibit metabolic disorders mediated by insulin resistance orhyperglycemia in a patient in need thereof. Further included in thisinvention is a method of modulating blood glucose levels in a patient inneed thereof.

Each of these methods comprises administering to a patient in needthereof pharmaceutically effective amounts of:

-   -   a) a PTPase inhibiting agent of formula I; and    -   b) a biguanide agent; and    -   c) optionally, a sulfonylurea agent.

Biguanide agents useful with this invention include metformin and itspharmaceutically acceptable salt forms. Sulfonylurea agents useful forthe methods and combinations of this invention may be selected from thegroup of glyburide, glyburide, glipizide, glimepiride, chlorpropamide,tolbutamide, or tolazamide, or a pharmaceutically acceptable salt formof these agents.

This invention also provides pharmaceutical compositions and methods ofusing PTPase inhibitors of formula I in combination with one or morealpha-glucosidase inhibitors, such as miglitol or acarbose, forimproving the cardiovascular risk profile in patients experiencing orsubject to Syndrome X or type II diabetes (non-insulin-dependentdiabetes mellitus), preferably in human type II diabetics. These methodsmay also be characterized as the reduction of risk factors for heartdisease, stroke or heart attack in a patient in such need.

These methods include the reduction of hyperlipidemia in type IIdiabetics, including methods in type II diabetics for lowering lowdensity lipoprotein (LDL) blood levels and to increase high densitylipoprotein (HDL) blood levels. The methods herein may further becharacterized as useful for inhibiting, preventing or reducingatherosclerosis in a type II diabetic or a patient experiencing orsubject to Syndrome X, or the risk factors of either.

These methods also include the lowering free fatty acid blood levels andtriglyceride levels in type II diabetics, or a patient experiencing orsubject to Syndrome X.

Among the alpha-glucosidase inhibitors which may be utilized with theinvention described herein are miglitol or acarbose, or apharmaceutically acceptable salt form of one or more of these compounds.

This invention further provides methods for using a PTPase inhibitor ofthe invention and a sulfonylurea agent for the management of Syndrome Xor type 2 diabetes and for improving the cardiovascular risk profile inpatients experiencing or subject to those maladies. These methods mayalso be characterized as the reduction of risk factors in such patientsfor heart disease, stroke or heart attack in a type II diabetic. Suchmethods include the reduction of hyperlipidemia in a patientsexperiencing or subject to Syndrome X or type II diabetes and includemethods for lowering low density lipoprotein (LDL) blood levels, highdensity lipoprotein (HDL) blood levels, and overall blood lipoproteinlevels. The methods herein may further be characterized as inhibiting,preventing or reducing atherosclerosis in patients subject to orexperiencing Syndrome X or type II diabetes, or the risk factorsthereof. Such methods further include the lowering of free fatty acidblood levels and triglyceride levels in such patients.

Representative sulfonylurea agents include glipizide, glyburide(glibenclamide), chlorpropamide, tolbutamide, tolazamide andglimepriride, or the pharmaceutically acceptable salt forms thereof.

In addition, the invention provides combinations of a PTPase inhibitorof the invention and at least one thiazolidinedione agents. Suchcombinations are useful for treatment, inhibition or maintenance ofSyndrome X or type II diabetes in patients in need of such treatment.Accordingly, methods of using such combinations are provided by theinvention. Thus, the invention provides methods of using these agents totreat or inhibit metabolic disorders mediated by insulin resistance orhyperglycemia in patients in need thereof. Further included in thisinvention are methods of modulating blood glucose levels in a patient inneed thereof.

Each of these methods comprises administering to a patient in needthereof pharmaceutically effective amounts of:

-   -   a) a thiazolidinedione agent, such as selected from the group of        pioglitizone and rosiglitazone, or a pharmaceutically acceptable        salt form of these agents; and    -   b) a compound of formula I.

The invention also provides pharmaceutical compositions and methods ofusing PTPase inhibitors in combination with one or more antilipemicagents. Such methods and compositions are useful for improving thecardiovascular risk profile in patients experiencing or subject to typeII diabetes (non-insulin-dependent diabetes mellitus), preferably intype II diabetics or Syndrome X. These methods also include reducing therisk factors for heart disease, stroke or heart attack in a type IIdiabetic or a patient experiencing or subject to Syndrome X. Suchmethods further include the reduction of hyperlipidemia in type IIdiabetics, including such methods in type II diabetics for lowering lowdensity lipoprotein (LDL) blood levels and to increase high densitylipoprotein (HDL) blood levels. These compositions and methods are alsouseful for inhibiting, preventing or reducing atherosclerosis in a typeII diabetic or a patient experiencing or subject to Syndrome X, or therisk factors thereof. In this aspect, the compositions and methods areuseful for lowering of free fatty acid blood levels and triglyceridelevels in type II diabetics, or patients experiencing or subject toSyndrome X.

Representative antilipemic or agents, also known as antihyperlipidemicagents, suitable for use in the invention are bile acid sequestrants,fibric acid derivatives, HMG-CoA reductase inhibitors and nicotinic acidcompounds. Bile acid sequestrant agents useful with this inventioninclude colestipol and colesevelam, and their pharmaceuticallyacceptable salt forms. Fibric acid derivatives which may be used withthe present invention include clifofibrate, gemfibrozil and fenofibrate.HMG-CoA reductase inhibitors, also known as statins, useful with thisinvention include cerivastatin, fluvastatin, atorvastatin, lovastatin,pravastatin and simvastatin, or the pharmaceutically acceptable saltforms thereof. Niacin is an example of a nicotinic acid compound whichmay be used with the methods of this invention. Also useful are lipaseinhibiting agents, such as orlistat.

This invention also provides pharmaceutical compositions that are acombination of a compound of Formula I and an aldose reductase inhibitor(ARI). Such combinations are useful in methods for treating, inhibitingor preventing type II diabetes, or its related and associated symptoms,disorders and maladies. These methods comprise administering to apatient in need of such therapy a pharmaceutically effective amount of acomposition comprising a combination of pharmaceutically effectiveamounts of a compound of formula I and an ARI. These compositions andmethods are useful for the treatment, prevention or inhibition ofdiabetic neuropathy, diabetic nephropathy, retinopathy, keratopathy,diabetic uveitis, cataracts.

Representative suitable ARIs are disclosed in U.S. Pat. Nos. 6,420,426and 6,214,991.

Combinations of the compounds of Formula I and an ARI are also usefulfor inhibition or reduction of risk factors for heart disease, stroke orheart attack in a type II diabetic. Therefore, in this aspect theinvention is useful for reducing hyperlipidemia and/or low densitylipoprotein (LDL) blood levels in type II diabetics. Also included inthis aspect are methods for inhibiting, preventing or reducingatherosclerosis or the risk factors thereof in type II diabetics. Thisaspect includes lowering of free fatty acid blood levels andtriglyceride levels.

This invention also provides methods of using a compound of formula Iand insulin(s) for the management of type I or type II diabetes.Accordingly, the invention provides for combination therapy, i.e., wherea compound of Formula I is administered in combination with insulin.Such combination therapy encompasses simultaneous or sequentialadministration of the compound of Formula I and insulin. The insulinsuseful in this aspect include both naturally occurring and syntheticinsulins.

Insulins useful with the methods and combinations of this inventioninclude rapid acting insulins, intermediate acting insulins, long actinginsulins and combinations of intermediate and rapid acting insulins.

Rapid acting commercially available insulin products include HUMALOG®Brand Lispro Injection (rDNA origin); HUMULIN® Regular Human Injection,USP [rDNA origin]; HUMULIN® Regular U-500 Concentrated Human Injection,USP [rDNA origin]; REGULAR ILETIN® II (insulin injection, USP, purifiedpork) available from Eli Lilly and Co.; and the NOVALIN® Human InsulinInjection and VENOSULIN® BR Buffered Regular Human Injection, eachavailable from Novo Nordisk Pharmaceuticals.

Commercially available intermediate acting insulins useful with thisinvention include, but are not limited to, the HUMULIN® L brand LENTE®human insulin [rDNA origin] zinc suspension, HUMULIN® N NPH humaninsulin [rDNA origin] isophane suspension, LENTE® ILETIN.RTM. II insulinzinc suspension, USP, purified pork, and NPH ILETIN® II isophane insulinsuspension, USP, purified pork, available from Eli Lilly and Company,LANTUS® insulin glargine [rDNA origin] injection, available from AventisPharmaceuticals, and the NOVOLIN L Lente® human insulin zinc suspension(recombinant DNA origin), and NOVOLIN® N NPH human insulin isophanesuspension (recombinant DNA origin) products available from Novo NordiskPharmaceuticals, Inc, Princeton N.J.

Also useful with the methods and formulations of this invention areintermediate and rapid acting insulin combinations, such as the HUMALOG®Mix 75/25 (75% Insulin Lispro Protamine Suspension and 25% InsulinLispro Injection), HUMULIN® 50/50 (50% Human Insulin Isophane Suspensionand 50% Human Insulin Injection) and HUMULIN® 70/30 (70% Human InsulinIsophane Suspension and 30% Human Insulin Injection), each availablefrom Eli Lilly and Company. Also useful are the NOVALIN® 70/30 (70% NPH,Human Insulin Isophane Suspension and 30% Regular, Human InsulinInjection) line of combination products available from Novo NordiskPharmaceuticals.

A commercially available long acting insulin for use with this inventionis the HUMULIN® U Ultralente® human insulin [rDNA origin] extended zincsuspension, available from Eli Lilly and Company.

Also useful in the methods of this invention are inhaled insulinproducts, such as the EXUBERA® inhaled insulin product developed byPfizer Inc. and Aventis SA.

Each of these insulin products can be administered as directed by amedical professional using administrations, dosages and regimens knownin the art, such as those published for each product in the Physicians'Desk Reference, 55 Edition, 2001, published by Medical EconomicsCompany, Inc. at Montvale, N.J., the relevant sections of which areincorporated herein by reference.

In this aspect, the invention includes, for example, methods forimproving the cardiovascular and cerebrovascular risk profiles inpatients experiencing or subject to type I or type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics. These methods may also be characterized as the inhibition orreduction of risk factors for heart disease, stroke or heart attack in atype II diabetic.

The compounds of the present invention may be prepared by use of knownchemical reactions and procedures. Representative methods forsynthesizing compounds of the invention are presented below. It isunderstood that the nature of the substituents required for the desiredtarget compound often determines the preferred method of synthesis. Allvariable groups of these methods are as described in the genericdescription if they are not specifically defined below.Methods of Preparation

Scheme I illustrates the preparation of compounds of the inventionwherein the B-ring is a pyrazole or a dihydropyrazole, and the A-ring isan unsubstituted dibenzofuran.

One of skill in the art will appreciate that A-rings may be placed inthe molecule, including phenyl, indole, or dibenzofuran. Furthermore,other coupling reactions, such as the Heck or Stille reactions, may beused to effect the coupling of the A-ring to the core.

Scheme 2 illustrates the synthesis of compounds of the invention whereinthe B-ring is a pyridinone ring, and the A-ring is dibenzofuran.

One of skill in the art will appreciate that other A-rings may be placedin the molecule, including phenyl, indole or dibenzofuran. Furthermore,other coupling reactions, such as the Heck or Stille reactions, may beused to effect the coupling of the A-ring to the core.

Those having skill in the art will recognize that the starting materialsand reaction conditions may be varied, the sequence of the reactionsaltered, and additional steps employed to produce compounds encompassedby the present invention, as demonstrated by the following examples. Insome cases, protection of certain reactive functionalities may benecessary to achieve some of the above transformations. In general, theneed for such protecting groups as well as the conditions necessary toattach and remove such groups will be apparent to those skilled in theart of organic synthesis.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference intheir entirety.

The preparation of the compounds of the present invention is illustratedfurther by the following examples, which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them. In all cases, unless otherwise specified,the column chromatography is performed using a silica gel solid phase.

EXAMPLE 1[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid

Step 1: Preparation of 1-(4-Bromo-phenyl)-3-(4-methoxy-phenyl)-propenone

A solution of 4-bromoactophenone (8.0 g, 4.0 mmol) and4-methoxybenzaldehyde (5.1 mL, 4.2 mmol) in dry methanol (25 mL) wastreated with sodium methoxide (2.26 g, 4.2 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was acidified with 0.5 N HCl(25 mL). The resulting precipitate was collected by filtration andwashed with a 50% aq methanol solution (3×25 mL) to give1-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-propenone as a white crystallinesolid (98%).

Step 2: Preparation of[5-(4-Bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid ethyl ester

A solution of ([1-(4-bromophenyl)-3-(4-methoxypheyl)-propene]) (3.17 g,10 mmol) and ethyl hydrazinoacetate hydrochloride (1.54 g, 10 mmol) inethanol (50 mL) was heated to reflux for 4 h. After cooling to roomtemperature, the solution was concentrated, diluted with water (50 mL)and extracted with ethyl acetate (3×50 mL). The combined organicextracts were dried over MgSO4, filtered and concentrated. Purificationby flash column chromatography (5-10% ethyl acetate in heptane) provided[5-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid ethyl ester (3.25 g, 78%) as an oil.

Step 3: Preparation of[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid ethyl ester

A solution of[5-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid ethyl ester (0.417 g, 1.0 mmol) and 4-dibenzofuranboronic acid(0.233 g, 1.1 mmol) in toluene (15 mL, X M) was treated with 2 N aqK2CO3 (1.5 mL, xx mmol) and Pd[PPh3]4 (0.058 g, 0.05 mmol). Theresulting solution was heated to reflux for 2 h, cooled to roomtemperature, diluted with water (50 mL) and extracted with ethyl acetate(3×50 mL). The combined organic extracts were dried over MgSO4, filteredand concentrated. Purification by flash column chromatography (10% ethylacetate in heptane) provided[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid ethyl ester (0.394 g, 78%) as a white crystalline solid.

Step 5:[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid

A solution of[5-(4-dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid ethyl ester (0.120 g, 0.275 mmol) in THF (2 mL) and methanol (6 mL)was treated with 10% aq KOH (0.5 mL, 1 mmol) and stirred at roomtemperature. After 2 h, the solution was acidified with 0.5 N HCl to PH2-3 and extracted with ethyl acetate (3×15 mL). Purification by flashcolumn chromatography (50% ethyl acetate in heptane) provided[5-(4-dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid (0.108 g, 95%) as a white crystalline solid.

EXAMPLE 2[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-aceticacid Step 1: Preparation of[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-aceticacid ethyl ester

A solution of[5-(4-dbenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid ethyl ester (0.250 g, 0.495 mmol) in benzene (20 mL) was treatedwith DDQ (0.17 g, 15 mmol) and heated to reflux for 6 h. After coolingto room temperature, the reaction mixture was concentrated and purifiedby flash column chromatography (5-10% ethyl acetate in heptane) to give[5-(4-dbenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-aceticacid ethyl ester (0.236 g, 95%) as a white crystalline solid.

Step 2:[5-(4-benzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-aceticacid

A solution of[5-(4-dbenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-aceticacid ethyl ester (0.200 g, 0.4 mmol) in THF (2 mL) and methanol (6 mL)was treated with 10% aq KOH (1 mL, 2 mmol) and stirred at roomtemperature. After 2 h, the solution was acidified with 0.5 N HCl to PH2-3 and extracted with ethyl acetate (3×15 mL). Purification by flashcolumn chromatography (50% ethyl acetate in heptane) providedbenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetic acid(178 g, 95%) as a white crystalline solid.

EXAMPLE 3N-[4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamicacid Step 1: (4-Bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone

A solution of 2-n-butylbenzofurane (19.8 g, 114 mmol) and 4-bromobenzoylchloride (25.0 g, 114 mmol) in dry dichloromethane (300 mL, 0.4 M) wascooled to 0° C. and treated with AlCl₃ (16.6 g, 1.1 equiv., 125.4 mmol)in 3 portions. After the additions were complete, the solution wasstirred for 3 h and carefully added to ice water. After separation, theaqueous layer was extracted with dichloromethane (2×200 mL) and thecombined organic layers were washed with water, sat'd aq NaCl, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. Purificationby flash column chromatography (1-2% ethyl acetate in heptane) afforded(4-bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone (14.6 g, 36%).

Step 2: 3-(4-Bromo-benzyl)-2-butyl-benzofuran

A solution of (4-bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone (2.25g, 6.32 mmol) in ethanol (20 mL, 0.3 M) was cooled to 0° C. and treatedwith NaBH₄ (0.263 g, 1.1 equiv, 6.95 mmol). After stirring for 1 h, themixture was poured into a 50% ether in water solution (200 mL). Afterseparation, the aqueous layer was extracted with ether (50 mL) and thecombined organic layers were washed with water, sat'd aq NaCl, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The resultingalcohol was subsequently dissolved in dry dichloromethane (50 mL),cooled to 0° C. and treated with triethylsilane (2.0 mL, 2.0 equiv.,12.64 mmol) dropwise via syringe. After stirring an additional 5 min,trifluoroacetic acid (2.43 mL, 5.0 equiv., 31.6 mmol) was added over 2min and the mixture was stirred for 3 h. Once complete, the solution waswashed with water, sat'd aq NaCl, dried over anhydrous MgSO₄, filteredand concentrated in vacuo. Purification by flash column chromatography(0-2% ethyl acetate in heptane) afforded3-(4-bromo-benzyl)-2-butyl-benzofuran as a pale yellow oil (1.34 g,63%).

Step 3:2-Butyl-3-[4-(4,4,5,5-tetramethyl-(1,3,2]dioxaborolan-2-yl)-benzyl]-benzofuran

A solution of 3-(4-bromo-benzyl)-2-butyl-benzofuran (14.03 g, 41.5mmol), bis(pinacolato)diborane (11.60 g, 1.1 equiv., 45.7 mmol),potassium acetate (12.2 g, 3.0 equiv., 125 mmol) in DMSO (100 mL, 0.4 M)was treated with PdCl₂(dppf).CH₂Cl₂ (4.15 g, 0.1 equiv., 4.15 mmol) andheated to 80° C. After compete by TLC, the solution was coled to roomtemperature, diluted with water (150 mL) and filtered through celite(washed with ether, 500 mL). After separation, the aqueous layer wasextracted with ether (2×150 mL). The combined organic layers were washedwith water, sat'd aq NaCl, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification by flash column chromatography (2-5%ethyl acetate in heptane) afforded2-butyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-benzofuranas a pale yellow oil (11.2 g, 69%).

EXAMPLE 4N-[1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamicacid Step 1: (4-Dibenzofuran-4-yl-phenyl)-trimethyl-silane

A solution of dibenzofuran-4-yl-boronic acid (20.0 g, 94.3 mmol),(4-bromo-phenyl)-trimethyl-silane (21.62 g, 94.3 mmol), K₂CO₃ (39.1 g, 3equiv., 283 mmol) in toluene (100 mL), ethanol (60 mL) and water (30 mL)was purged with nitrogen for 5 min (bubbled into solution) and treatedwith Pd(PPh₃)₄ (3.59 g, 2.9 mmol). After heating to 80° C. for 4 h, thesolution was cooled to room temperature, poured into water (300 mL) andextracted with ethyl acetate (300 mL). The organic phase was washed withsat'd aq NaCl, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification by flash column chromatography (5-20% ethyl acetatein heptane) afforded (4-dibenzofuran-4-yl-phenyl)-trimethylsilane as acolorless oil (28.9 g, 96%).

Step 2: 4-Dibenzofuran-4-yl-phenyl-boronic acid

A solution of (4-dibenzofuran-4-yl-phenyl)-trimethyl-silane (28 6 g,90.2 mmol) in dichloromethane (350 mL, 0.26 M) was cooled to −78° C. andcarefully treated with borontribromide (135 mL, 1.5 equiv., 135 mmol).After the addition was complete, the solution was warmed to roomtemperature and stirred for 3 h. Next, the reaction mixture wasre-cooled to −78° C., treated with dry methanol (30 mL), slowly warmedto room temperature and stirred for 1.5 h. Next, the solution wasre-cooled to −78° C., carefully quenched with 10% aq HCl (50 mL), warmedto room temperature and stirred for 1 h (solids form). The resultingsolution was poured into water (500 mL) and extracted with ethyl acetate(3×700 mL). The combined organic layers were washed with sat'd aq NaCl,dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude product was suspended in a 10% ethyl acetate in heptane solution,filtered and washed with the same solution (5×60 mL) to give4-dibenzofuran-4-yl-phenyl-boronic acid as a white solid (20.2 g, 77%).

Step 3: 1-Benzyl-5-bromo-3-nitro-1H-pyridin-2-one

A solution of 5-bromo-3-nitro-pyridin-2-ol (5.0 g, 22.8 mmol) and K₂CO₃(9.5 g, 3 equiv., 69 mmol) in DMF (25 mL) was treated with benzylbromide (4.3 g, 1.1 equiv., 25 mmol) and heated to 50° C. After stirringovernight, the solution was poured into water (150 mL) and extractedwith ethyl acetate (2×150 mL). The combined organic layers were washedwith sat'd aq NaCl, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification by flash column chromatography(30-40% ethyl acetate in heptane) afforded1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one as a yellow solid (5.56 g,79%).

Step 4: 1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-3-nitro-1H-pyridin-2-one

A solution of 1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one (1.0 g, 3.24mmol), 4-dibenzofuran-4-yl-phenyl-boronic acid (932 mg, 3.24 mmol),K2CO3 (1.34 g, 3 equiv., 9.7 mmol) in toluene (15 mL), ethanol (10 mL)and water (5 mL) was treated with treated with Pd(PPh₃)₄ (125 mg). Afterheating to 80° C. overnight, the solution was cooled to room temperatureand the resulting solids were filtered and washed with ether (2×6 mL) togive 1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-3-nitro-1H-pyridin-2-one asa yellow solid (1.53 g, 92%).

Step 5: 3-Amino-1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-1H-pyridin-2-one

1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-3-nitro-1H-pyridin-2-one (100mg, 0.212 mmol) was dissolved in hot 50% ethanol in DMF (8 mL) andcooled to room temperature. 10% Pd—C (10 mg) was added and the solutionwas shaken on a Parr hydrogenator with 60 psi H₂ for 2 h. The resultingmixture was diluted with water (30 mL) and ethyl acetate (70 mL),separated and extracted with ethyl acetate (100 mL). The combinedorganic layers were washed with sat'd aq NaCl, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to give3-amino-1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-1H-pyridin-2-one as ayellow sold that was used without further purification.

Step 6:N-[1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamicacid ethyl ester

A solution of3-amino-1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-1H-pyridin-2-one (250mg, 0.565 mmol), triethylamine (0.24 mL, 3.0 equiv., 1.7 mmol), indichloromethane (5 mL) was cooled to 0° C. and treated with ethylchlorooxylate (0.10 mL, 1.1 equiv., 0.622 mmol). After 10 min, thereaction mixture was warmed to room temperature a stirred for 2 h. Theresulting solution was partially concentrated and subsequently purifidedby by flash column chromatography (30-75% ethyl acetate in heptane)affordedN-[l-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamicacid ethyl ester (0.218 mg, 71%).

Step 7:N-[1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamicacid

A solution ofN-[1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamicacid ethyl ester (110 mg, 0.203 mmol) in 1,4-dioxane (4 mL) was treatedwith NaOH (24 mg, 3 equiv., 0.6 mmol) and stirred at room temperature.After 4 h, the solution was acidified with 10% HCl to pH<5. Theresulting precipitate was filtered and washed with ether (2×2 mL) togiveN-[1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamicacid as a white solid (102.4 mg, 99%). Mp 220-223° C.; Rf 0.63 (50%methanol in ethyl acetate), ¹H NMR (DMSO-d₆, 300 MHz) δ 10.36 (s, 1 H),8.74 (d, J=2.4 Hz, 1 H), 8.20-7.99 (m, 5 H), 7.72, (dd, J1=10.2 Hz,J2=8.1 Hz, 4 H), 7.53-7.28 (m, 7 H), 5.28 (s, 2 H) ); ESI-LCMS m/z calcdfor C₃₂H₂₂N₂O₅: 514; found 515 (M+1)⁺.

EXAMPLE 51-{4-[4-(4-Chloro-phenyl)-5-(4-ethyl-phenyl)-thiazol-2-ylcarbamoyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid

Mp 289-292° C.; R_(f) 0.08 (20% methanol in dichloromethane)

EXAMPLE 6 4-Hydroxy-N-tert-butoxycarbonyl-proline methyl ester

A solution of 4-hydroxyproline (7.54 g, 42 mmol) and triethylamine (14.7mL, 105 mmol) in 50% aqueous acetone (50 mL) was cooled to 0° C. andtreated with di-tert-butyl dicarbonate (10.1 g , 46.4 mmol). After theaddition was complete, the reaction mixture was stirred for 16 h andconcentration to yield 10.5 g crude4-Hydroxy-N-tert-butoxycarbonyl-proline methyl ester as solid which canbe used without further purification. A pure sample can be obtained byrecrystalization with 50% ethyl acetate in heptane. ¹H NMR (CDCl₃), 4.52(b, 1 H), 4.41 (dd, J=6, 8 Hz, 1 H), 3.73 (s, 3 H), 3.64 (dd, J=1, 8 Hz,1 H), 3.50 (m, 1 H), 2.28 (m, 1 H), 2.08 (m, 2 H), 1.46 (s, 9 H)

EXAMPLE 74-(4′-dibenzofuran-4-yl-biphenyl-4-yloxy)-N-tert-butoxycarbonyl-proline 1.4-Methylsulfonyloxy-N-tert-butoxycarbonyl-proline methyl ester

A solution of 4-hydroxy-N-tert-butoxycarbonyl-proline methyl ester (5.89g, 24 mmol) and triethylamine (4 mL, 28.8 mmol) in dichloromethane (80mL) was cooled to 0° C. and treated with methylsulfonyl chloride (2.1mL). After stirring an additional 2 h, the reaction mixture wasacidified with 2% HCl (20 mL) and extracted with dichloromethane (3×20mL). The combined organic layers were washed successively with sat. aqNaHCO₃, and sat. aq NaCl, dried over MgSO₄ and concentrated.Purification by flash column chromatography (5% ethyl acetate inheptane) gave 4-methylsulfonyloxy-N-tert-butoxycarbonyl-proline methylester. ¹H NMR (CDCl₃), 5.25 (m, 1 H), 4.41 (m, 1 H), 3.78 (m, 5 H), 3.06(s, 3 H), 2.61 (m, 1 H), 2.22 (m, 1 H), 1.46 (s, 9 H).

2. 4-(4′-bromophenylsulfanyl)-N-butoxycarbonyl-proline methyl ester

A solution of 4-methylsulfonyloxy-N-tert-butoxycarbonyl-proline methylester (2 g, 6.19 mmol) and 4-bromobenzenthiol (1.17 g, 6.19 mmol) in DMF(25 mL) was cooled to 0° C. and treated with Cs₂CO₃ (2.2 g, 6.8 mmol).After stirring at room temperature for 2 h, the reaction mixture wasacidified with 5% HCl (25 mL). After separating, the aqueous layer wasextracted with ethyl acetate (3×25 mL) and the combined organic layerswere washed with sat. aq NaCl, dried over MgSO₄ and concentrated.Purification by flash column chromatography (5% ethyl acetate inheptane) gave 4-(4′-bromophenylsulfanyl)-N-butoxycarbonyl-proline methylester (1.57 g, 61%) as white solid. ¹H NMR (CDCl₃), δ 7.42 (m, 2 H),7.24 (m, 2 H), 4.26 (ddd, J=8, 8, 24 Hz, 1 H), 3.92 (m, 1 H), 3.76 (s, 3H), 3.59 (m, 1 H), 3.36 (m, 1 H), 2.60 (m, 1 H), 2.03 (m, 1 H), 1.44 (s,9 H).

3.4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfanyl)-N-tert-butoxycarbonyl-prolinemethyl ester

A solution of 4-(4′-bromophenylsulfanyl)-N-tert-butoxycarbonyl-prolinemethyl ester (416 mg, 1 mmol), (4-Dibenzofuran-4-yl-phenyl)boronic acid(302 mg, 1.05 mmol), Pd(PPh₃)₄ (52 mg, 5% mol) in toluene (10 mL) andethanol (2.5 mL) was heated until the solution became clear andsubsequently treated with 2 M K₂CO₃ (1.5 mL). The reaction mixture washeated to reflux for 2 h, cooled to room temperature, diluted with ethylacetate (100 mL). The organic layer was washed successively with 2% aqHCl and sat. aq NaCl, dried over MgSO₄ and concentrated. Purification byflash column chromatography (2-10% ethyl acetate in heptane) to give4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfanyl)-N-tert-butoxycarbonyl-prolinemethyl ester (410 mg, 73%). ¹H NMR (CDCl₃), δ 8.01 (m, 3 H), 7.95 (d,J=6 Hz, 1 H), 7.73 (d, J=7 Hz, 2 H), 7.62 (m, 4 H), 7.41 (m 5 H),4.37-4.28 (m, 1 H), 4.01 (m, 1 H), 3.76 (s, 3 H), 3.69 (m, 1 H), 3.42(m, 1 H), 2.67 (m, 1 H), 2.07 (m, 1 H), 1.44 (s, 9 H). LCMS 580 (M⁺+1).

4.4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfnayl)-N-tert-butoxycarbonyl-proline

A solution of4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfnayl)-N-tert-butoxycarbonyl-prolinemethyl ester (0.25 g, 0.44 mmol) in THF (2 mL) and methanol (2 mL) wascooled to 0° C. and treated with 2 N KOH (1 mL). After stirring at roomtemperature for 1 h the solution was acidified with 10% HCl to pH 2 anddiluted with 25 ml of ethyl acetate. After being separated, the aqueouslayer was extracted with ethyl acetate (3×15 mL) and the combinedorganic layers were dried over MgSO₄ and concentrated. Purification byflash column chromatography (2-5% methanol in dichloromethane) provided4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfnayl)-N-tert-butoxycarbonyl-proline(120 mg, 50%). as pale yellow solid. ¹H NMR (CDCl₃), δ 8.03 (m, 4 H),7.80 (d, J=9 Hz, 2 H), 7.80 (d, J=9, 2 H), 7.69 (d J=9 Hz, 2 H), 7.47(m, 5 H), 4.29 (t, J=9 Hz, 1 H), 3.92 (m, 2 H), 3.72 (m, 1 H), 2.72 (m,1 H), 2.05 (m, 1 H), 1.44 (s, 9 H). LCMS 460 (M⁺−100).

EXAMPLE 8 4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-proline 1.4-(4′-bromobiphen-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester

A solution of DEAD (1.6 mL, 9.8 mmol) in benzene (10 mL) was added to asecond solution of 4-hydroxy-N-tert-butoxycarbonyl-proline methyl ester(2.2 g, 8.97 mmol) and triphenylphosphine (2.6 g, 9.87 mmol) in benzene(20 mL) and THF (5 mL) cooled to 0° C. After the addition was complete,the reaction mixture was warmed to room temperature and stirred for 16h, quenched with water (20 mL) and extracted with ethyl acetate (3×20mL). The combined organic layers were washed with sat. aq NaHCO₃, andsat. aq NaCl, dried over MgSO₄ and concentrated. Purification by flashcolumn chromatography (5-25% ethyl acetate in heptane) provided4-(4′-bromobiphen-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester(3.2 g, 77%) as white solid. ¹H NMR (CDCl₃), δ 7.39 (m, 6 H), 6.84 (dd,J=3, 9 Hz, 2 H), 4.94 (m, 1 H), 4.46 (m, 1 H), 3.77 (m, 5 H), 2.51 (m, 2H), 1.44 (s, 9 H).

2.4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-prolinemethyl ester

A solution of 4-(4′-bromobiphen-4-yloxy)-N-tert-butoxycarbonyl-prolinemethyl ester (476 mg, 1 mmol), 4-dibenzofuranylboronic acid (222 mg,1.05 mmol) and Pd(PPh₃)₄ (52 mg, 5% mol) in toluene (10 mL) and ethanol(2.5 mL) was heated until the solution became clear and subsequentlytreated with 2 M K₂CO₃ (1.5 mL). The reaction mixture was heated toreflux for 2 h, cooled to room temperature, diluted with ethyl acetate(100 mL). The organic layer was washed successively with 2% aq HCl andsat. aq NaCl, dried over MgSO₄, filtered and concentrated. Purificationby flash column chromatography (2-10% ethyl acetate in heptane) gave4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-prolinemethyl ester (423 mg, 75%) as a foam. ¹H NMR (CDCl₃), δ 7.97 (m, 4 H),7.71 (dd, J=1, 8 Hz, 2 H), 7.62 (m, 4 H), 7.45 (m, 3 H), 6.90 (dd, J=1,9 Hz, 2 H), 4.96 (m, 1 H), 4.52 (m, 1 H), 3.78 (m, 5 H), 2.52 (m, 2 H),1.46 (s, 9 H). LCMS 464 (M⁺−100).

3.4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-proline

A solution of4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-prolinemethyl ester (400 mg, 0.71 mmol) in THF (3 mL) and methanol (4 mL) wascooled to 0° C. and treated with 2 N KOH (1.25 mL). After stirring atroom temperature for 1 H the solution was acidified with 10% HCl to pH 2and diluted with 25ml of ethyl acetate. After being separated, theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic layers were dried over MgSO₄ and concentrated.Purification by flash column chromatography (2-5% methanol indichloromethane) provided4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-butoxycarbonyl-proline (320mg, 82%) as pale yellow solid. 0.320 g (yield 82.1%) . ¹H NMR (DMSO-d₆),δ 8.16 (dd, J=8, 12 Hz, 2 H), 7.98 (d, J=9 Hz, 2 H), 7.80 (m, 6 H), 7.47(m, 3 H), 6.97 (d, J=9 Hz, 2 H), 5.08 (m, 1 H), 4.29 (t, J=9 Hz, 1 H),3.72 (m, 1 H), 3.42 (dd, J=6, 9 Hz, 1 H), 2.62 (m, 1 H), 2.20 (m, 1 H),1.44 (s, 9 H). LCMS 450 (M⁺−100).

EXAMPLE 9[[5-(4-Dibenzofuran-4-yl-phenyl)-thiophene-2-sulfonyl]-(3-trifluoromethyl-benzyl)-amino]-aceticacid

Isolated as a white solid. R_(f) 0.20 (10% Methanol-90% MethyleneChloride); ¹H NMR (DMSO-d₆) 8.18 (t, J=7.2Hz, 2H), 8.02 (d, J=8.7 Hz,2H), 7.90 (d, J=8.4 Hz, 2H), 7.82 (d, J=3.9 Hz, 1H), 7.75 (m, 2H), 7.67(d, J=3.9 Hz, 1H), 7.63-7.40 (m, 7H), 4.64 (s, 2H), 4.64 (s, 2H).

EXAMPLE 104-[1-(4,6-bis-Dimethylamino-[1,3,5]-triazin-2-yl)-5-bromo-1H-indol-3-yl]-4-oxo-butyricacid

A solution of 4-(5-bromo-1H-indol-3-yl)-4-oxobutyric acid (148 mg, 0.5mmol) in anhydrous dimethylformamide (5 mL) was added dropwise to astirred suspension of sodium hydride (95%, 50 mg, 2.0 mmol) indimethylformamide (5 mL). After 30 mins, a solution ofN2,N2,N4,N4-tetramethyl-6-chloro-[1,3,5]-triazine-2,4-diamine (100 mg,0.5 mmol) in dimethylformamide (5 mL) was added dropwise. The reactionmixture was stirred at 70° C. for 16 hours, cooled to room temperatureand then poured carefully into water (20 mL), acidified to pH 4 with0.5N hydrochloric acid and extracted with ethyl acetate (3×25 mL). Thecombined extract was washed with water, brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Purification by flash columnchromatography (5% methanol in dichloromethane) afforded the titlecompound as a white solid (111 mg, 48%), Rf: 0.40 (10% methanol indichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.96 (1H, s, ArH), 8.55(1H, d, J=9 Hz, ArH), 8.33 (1H, d, J=2 Hz, ArH), 7.47 (1H, dd, J=9, 2Hz, ArH), 3.22 (2H, t, J=7 Hz, CH₂), 3.18 (6H, s, 2×Me), 3.12 (6H, s,2×Me), 2.59 (2H, t, J=7 Hz, CH₂); ESI-LCMS e/z calculated forC₁₉H₂₁BrN₆O₃ 461.318, found 461 [M+H (⁷⁹Br)]⁺, 463 [M+H (⁸¹Br)]⁺, 483[M+Na (⁷⁹Br)]⁺, 485 [M+Na (⁸¹Br)]⁺.

EXAMPLE 114-{5-Bromo-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl)-1H-indol-3-yl]-4-oxo-butyricacid

A solution of 4-(5-bromo-1H-indol-3-yl)-4-oxobutyric acid (148 mg, 0.5mmol) in anhydrous dimethylformamide (5 mL) was added dropwise to astirred suspension of sodium hydride (95%, 50 mg, 2.0 mmol) indimethylformamide (5 mL). After 30 mins, a solution ofl-(4-chloro-6-tetrahydro-1H-pyroll-1-yl-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydroquinoline(158 mg, 0.5 mmol) in dimethylformamide (5 mL) was added dropwise. Thereaction mixture was stirred at 70° C. for 16 hours, cooled to roomtemperature and then poured carefully into water (20 mL), acidified topH 4 with 0.5N hydrochloric acid and extracted with ethyl acetate (3×25mL). The combined extract was washed with water, brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification byflash column chromatography (5% methanol in dichloromethane) affordedthe title compound as a white solid (221 mg, 77%), Rf: 0.30 (10%methanol in dichloromethane); ¹H NMR (THF-d8, 300 MHz) δ 8.78 (1H, s,ArH), 8.43 (1H, d, J=9 Hz, ArH), 8.36 (1H, d, J=2 Hz, ArH), 7.77 (1H, d,J=9 Hz, ArH), 7.20 (1H, dd, J=9, 2 Hz, ArH), 7.08 (1H, t, J=7 Hz, ArH),7.02 (1H, d, J=7 Hz), 6.92 (1H, t, J=7 Hz, Ar—H), 3.98 (2H, t, J=6 Hz,CH₂N), 3.45 (4H, br s, 2×CH₂N), 3.06 (2H, t, J=6 Hz, CH₂CO), 2.78 (1H,s, CHHN), 2.72 (2H, t, J=7 Hz, CH₂CO), 2.64 (1H, s, CHHN), 2.56 (2H, t,J=7 Hz, CH₂), 1.92 (4H, m, CH₂CH₂) ; ESI-LCMS e/z calculated forC₂₈H₂₇BrN₆O₃ 575.464, found 575 [M+H (⁷⁹Br)]⁺, 577 [M+H (⁸¹Br)]⁺, 597[M+Na (⁷⁹Br)]⁺, 599 [M+Na (⁸¹Br)]⁺.

EXAMPLE 124-{5-Chloro-1-[4-(2,3-dihydro-indol-1-yl)-6-piperidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid

Indoline (0.967 mL, 8.63 mmol) was added to a solution of sodium hydride(207 mg, 8.63 mmol) and anhydrous tetrahydrofuran (15 mL) in a flamedried flask at 0° C. stirred under nitrogen atmosphere. Fifteen minutesafter gas evolution had ceased, cyanuric chloride (1.59 g, 8.63 mmol)was added as a solid and the reaction was warmed to ambient temperatureand stirred under nitrogen. Upon completion (TLC 20% ethyl acetate inheptane), the reaction mixture was quenched with water and extractedwith ethyl acetate (3×). The combined extract was washed sequentiallywith water and brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo.

1-(4,6-Dichloro-[1,3,5]-triazin-2-yl)-2,3-dihydro-1H-indole (259 mg,0.970 mmol) was added as a solid to a stirred solution of piperidine(0.096 mL, 0.970 mmol) and triethylamine (0.203 mL, 1.45 mmol) intetrahydrofuran (10 mL). Upon completion (TLC 30% ethyl acetate inheptane), the reaction mixture was quenched with water and extractedwith ethyl acetate (3×). The combined extract was washed sequentiallywith water and brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo.

A reaction mixture of1-(4-chloro-6-piperidin-1-yl-[1,3,5]-triazin-2-yl)-2,3-dihydro-1H-indole(97 mg, 0.307 mmol), 4-(5-chloro-1H-indol-3-yl)-4-oxo-butyric acid2-trimethylsilanyl-ethyl ester (108 mg, 0.307 mmol), potassium carbonate(85 mg, 0.614 mmol) and DMAP (4 mg, 0.0307 mmol) in acetonitrile (30 mL)was stirred in a sealed tube at 80° C. Upon completion (TLC 30% ethylacetate in heptane), the reaction mixture was quenched with water andextracted with ethyl acetate (3×). The combined extract was washedsequentially with water and brine, dried over anhydrous MgSO₄, filtered,concentrated in vacuo and purified by flash chromatograhpy (Si0₂; 20%ethyl acetate in heptane as eluent).

To a stirred solution of4-{5-chloro-1-[4-(2,3-dihydro-indol-1-yl)-6-piperidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid 2-trimethylsilanyl-ethyl ester (0.198 g, 0.314 mmol) indichloromethane (3 mL) was added trifluoroacetic acid (0.25 mL, 3.25mmol). Upon completion (TLC 5% methanol in dichloromethane), thesolution was concentrated in vacuo to yield the titled compound as awhite solid. R_(f) 0.21 (5% methanol in dichloromethane); ¹H NMR(THF-d8, 300 MHz) 6 9.04 (1H, s, ArH), 8.73 (1H, d, J=9 Hz, ArH), 8.39(1H, d, J=2 Hz, ArH), 8.34 (1H, d, J=7 Hz, ArH), 7.32 (1H, dd, J=9, 2Hz, ArH), 7.23-7.16 (2H, m, ArH), 6.95 (1H, t, J=7 Hz, ArH), 4.40 (2H,m, CH₂), 3.97 (4H, m, CH₂), 3.28-3.18 (4H, m, CH₂, CH₂), 2.71 (2H, t,J=6 Hz, CH₂), 1.75-1.65 (6H, m, NCH₂); ESI-LCMS e/z calculated forC₂₈H₂₇ClN₆O₃ 530.183, found 531 (M+H)⁺, 553 (M+Na)⁺.

EXAMPLE 134-{5-Chloro-1-[4-(2,3-dihydro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid

4-{5-Chloro-1-[4-(2,3-dihydro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid was prepared in an analogous manner to that described previouslyexcept pyrrolidine was substituted for piperidine. R_(f) 0.19 (5%methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (1H, s,ArH), 8.59 (1H, d, J=9 Hz, ArH), 8. 26 (1H, d, J=7 Hz, ArH), 8.13 (1H,s, ArH), 7.33 (1H, dd, J=9, 2 Hz, ArH), 7.23-7.16 (2H, m, ArH), 6.96(1H, t, J=7 Hz, ArH), 4.19 (2H, m, CH₂), 3.55 (4H, m, CH₂), 3.18-3.06(4H, m, CH₂) 2.56 (2H, m, CH₂), 1.93 (4H, m, CH₂); ESI-LCMS e/zcalculated for C₂₇H₂₅ClN₆O₃ 516.168, found 517 (M+H)⁺, 539 (M+Na)⁺.

EXAMPLE 144-{5-Chloro-1-[4-(5-fluoro-2,3-dihydro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl)-4-oxo-butyricacid

4-{5-Chloro-1-[4-(5-fluoro-2,3-dihydro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl)-4-oxo-butyricacid was prepared in an analogous manner to that described previouslyexcept 5-fluoroindoline was substituted for indoline and pyrrolidine wassubstituted for piperidine. R_(f) 0.26 (5% methanol in dichloromethane);¹H NMR (DMSO-d6, 300 MHz) δ 8.87 (1H, s, ArH), 8.55 (1H, d, J=9 Hz,ArH), 8.17 (1H, m, ArH), 8.11 (1H, s, ArH), 7.31 (1H, dd, J=9, 2 Hz,ArH), 7.06 (1H, d, J=8 Hz, ArH), 6.98 (1H, td, J=9, 2 Hz, ArH), 4.19(2H, m, CH2), 3.53 (4H, m, CH₂) , 3.16-3.07 (4H, m, CH₂), 2.56 (2H, m,CH₂), 1.92 (4H, m, CH₂); ESI-LCMS e/z calculated for C₂₇H₂₄ClFN₆O₃534.158, found 535 (M+H)⁺, 557 (M+Na)⁺.

EXAMPLE 154-{5-Chloro-1-[4-(5-fluoro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid

4-{5-Chloro-1-[4-(5-fluoro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid was prepared in an analogous manner to that described previouslyexcept 5-fluoroindole was substituted for indoline and pyrrolidine wassubstituted for piperidine. R_(f) 0.21 (5% methanol in dichloromethane); ¹H NMR (THF-d8, 300 MHz) δ 9.04 (1H, s, ArH), 8.75-8.68 (2H, m, ArH),8.41-8.36 (2H, m, ArH), 7.32-7.26 (2H, m, ArH), 7.06 (1H, td, J=9, 2 Hz,ArH), 6.69 (1H, d, J=4 Hz, ArH), 3.74 (4H, m, CH₂), 3.24 (2H, t, J=6 Hz,CH₂), 2.70 (2H, t, J=6 Hz, CH₂), 2.08 (4H, m, CH₂); ESI-LCMS e/zcalculated for C₂₇H₂₂ClFN₆O₃ 532.143, found 533 (M+H)⁺, 555 (M+Na)⁺.

EXAMPLE 164-{5-Chloro-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid

4-{5-Chloro-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid was prepared in an analogous manner to that described previouslyexcept 1,2,3,4-tetrahydroquinoline was substituted for indoline and1,2,3,4-tetrahydroisoquinoline was substituted for piperidine. R_(f)0.31 (5% methanol in dichloromethane); ¹H NMR (THF-d8, 300 MHz) δ 8.94(1H, s, ArH), 8.54 (1H, t, J=8 Hz, ArH), 8.26 (1H, d, J=2 Hz, ArH), 7.78(1H, d, J=5 Hz, ArH), 7.16-6.96 (8H, m, ArH), 4.96 (1H, s, CHH), 4.88(1H, s, CHH), 4.12-3.99 (4H, m, CH₂), 3.14 (2H, t, J=7 Hz, CH₂), 2.90(2H, m, CH₂), 2.73 (2H, t, J=7 Hz, CH₂), 2.60 (2H, t, J=7 Hz, CH₂), 1.95(2H, m, CH₂); ESI-LCMS e/z calculated for C₃₃H₂₉ClN₆O₃ 592.199, found593 (M+H)⁺, 615 (M+Na)⁺.

EXAMPLE 174-{5-Chloro-1-[4-(3,4-dihydro-2H-quinolin-1-yl)-6-(4-phenyl-piperazin-1-yl)-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid

4-{5-Chloro-1-[4-(3,4-dihydro-2H-quinolin-1-yl)-6-(4-phenyl-piperazin-1-yl)-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid was prepared in an analogous manner to that described previouslyexcept 1,2,3,4-tetrahydroquinoline was substituted for indoline and4-phenylpiperazine was substituted for piperidine. R_(f) 0.32 (5%methanol in dichloromethane); 1H NMR (THF-d8, 300 MHz) δ 9.04 (1H, s,ArH), 8.61 (1H, d, J=9 Hz, ArH), 8.36 (1H, d, J=2 Hz, ArH), 7.85 (1H, d,J=8 Hz, ArH), 7.26-6.97 (8H, m, ArH), 6.80 (1H, t, J=8 Hz), 4.18-4.06(6H, m, CH₂), 3.28-3.21 (6H, m, CH₂), 2.83 (2H, t, J=7 Hz, CH₂), 2.69(2H, t, J=7 Hz, CH₂), 2.05 (2H, m, CH₂); ESI-LCMS e/z calculated forC₃₄H₃₂ClN₇O₃ 621.226, found 622 (M+H)⁺, 644 (M+Na)⁺.

EXAMPLE 184-{5-Chloro-1-[4-cyclopentyloxy-6-(3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid

Cyclopentanol (0.080 mL, 0.886 mmol) was added to a solution of sodiumhydride (0.021 g, 0.886 mmol) and anhydrous tetrahydrofuran (15 mL) in aflame dried flask at 0° C. stirred under nitrogen atmosphere. Fifteenminutes after gas evolution had ceased,1-(4,6-dichloro-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinoline(0.249 g, 0.886 mmol), as prepared in example 5, was added as a solidand the reaction was warmed to ambient temperature and stirred undernitrogen. Upon completion (TLC 20% ethyl acetate in heptane), thereaction mixture was quenched with water and extracted with ethylacetate (3×). The combined extract was washed sequentially with waterand brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo.

Arylation of 4-(5-chloro-1H-indol-3-yl)-4-oxo-butyric acid2-trimethylsilanyl-ethyl ester with1-(4-chloro-6-cyclopentyloxy-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinolineand subsequent hydrolysis as outlined previously yielded the titledcompound. R_(f) 0.30 (5% methanol in dichloromethane); ¹H NMR (DMSO-d6,300 MHz) δ 8.97 (1H, s, ArH), 8.55 (1H, d, J=9 Hz, ArH), 8.18 (1H, d,J=2 Hz, ArH), 7.81 (1H, d, J=8 Hz, ArH), 7.35-7.10 (4H, m, ArH), 5.44(1H, m, CH), 4.08 (2H, t, J=6 Hz, CH₂), 3.22 (2H, t, J=6 Hz, CH₂), 2.78(2H, t, J=6 Hz, CH₂), 2.58 (2H, t, J=6 Hz, CH₂), 2.01-1.61 (10H, m,CH₂); ESI-LCMS e/z calculated for C₂₉H₂₈ClN₅O₄ 545.183, found 546(M+H)⁺, 568 (M+Na)⁺.

EXAMPLE 194-{5-Chloro-1-[4-(3,4-dihydro-2H-quinolin-1-yl)-6-phenyl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyricacid

A solution of 1M phenylmagnesium bromide in tetrahydrofuran (1.00 mL,1.00 mmol) in a flame dried tube stirred under nitrogen atmosphere wasdiluted with tetrahydrofuran (25 mL). To this was added 1M ZnCl₂ intetrahydrofuran (1.00 mL, 1.00 mmol). After 0.5 hr stirring at ambienttemperature under nitrogen atmosphere1-(4,6-dichloro-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinoline(0.281 g, 1.00 mmol) and tetrakis-(triphenylphosphine) palladium(0)(0.069 mg, 0.060 mmol) were added and the reaction mixture was stirredin a sealed tube at 90° C. Upon completion (HPLC control), the reactionmixture was concentrated in vacuo and purified by flash chromatography(SiO₂; 1% ethyl acetate in heptane as eluent).

Arylation of 4-(5-chloro-1H-indol-3-yl)-4-oxo-butyric acid2-trimethylsilanyl-ethyl ester with1-(4-chloro-6-phenyl-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinolineand subsequent hydrolysis as outlined previously yielded the titledcompound. R_(f) 0.34 (5% methanol in dichloromethane); ¹H NMR (THF-d8,300 MHz) δ 9.21 (1H, s, ArH), 8.72 (1H, m, ArH), 8.59 (2H, d, J=7 Hz,ArH), 8.39 (1H, d, J=2 Hz, ArH), 7.95 (1H, d, J=8 Hz, ArH), 7.62-7.51(3H, m, ArH), 7.35-7.15 (4H, m, ArH), 4.32 (2H, t, J=6 Hz, CH₂), 3.30(2H, t, J=7 Hz, CH₂), 2.88 (2H, t, J=6 Hz, CH₂), 2.72 (2H, t, J=7 Hz,CH₂), 2.13 (2H, m, CH₂); ESI-LCMS e/z calculated for C₃₀H₂₄ClN₅O₃537.157, found 538 (M+H)⁺, 560 (M+Na)⁺.

EXAMPLE 20 4-[1-(4-Bromobenzyl)-5-chloro-1H-indol-3-yl]-4-oxo-butyricacid

A solution of methyl-(5-chloro-1H-indol-3-yl)-4-oxo-butyrate (650 mg,2.45 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise to astirred slurry of sodium hydride (95%, 68 mg, 2.7 mmol) intetrahydrofuran (10 mL). After 30 mins, a solution of 4-bromobenzylbromide (675 mg, 2.7 mmol) in tetrahydrofuran (10 mL) was added, and theresultant solution was stirred for 2 hours at 50° C., cooled to roomtemperature and then poured carefully into water (20 mL), acidified topH 4 with 0.5N hydrochloric acid and extracted with ethyl acetate (3×25mL). The combined extract was washed with water, brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification byflash column chromatography (50% ethyl acetate in heptane) afforded themethyl ester,methyl-4-[1-(4-bromobenzyl)-5-chloro-1H-indol-3-yl]-4-oxo-butyrate as acolorless oil.

2N Sodium hydroxide solution (0.21 mL, 0.42 mmol) was added dropwise toa stirred solution ofmethyl-4-[1-(4-bromobenzyl)-5-chloro-1H-indol-3-yl]-4-oxo-butyrate (59mg, 0.14 mmol) in tetrahydrofuran (5 mL) and methanol (1 mL). The clearreaction mixture was stirred at room temperature until the reaction wascomplete (TLC control), and then diluted with water (10 mL), andacidified to pH 3 with 2N hydrochloric acid. The reaction mixture wasextracted with ethyl acetate (2×20 mL). The combined extract was washedwith water, brine, dried over anhydrous MgSO₄, filtered and concentratedin vacuo. Purification of the product by flash column chromatography,using 5% methanol in methylene chloride as eluent, afforded the titlecompound as a white solid (56 mg, 95%): Rf: 0.30 (5% methanol indichloromethane); ¹H NMR (DMSO-d6, 300 MHz) δ 12.1 (1H, br s, OH), 8.67(1H, s, ArH), 8.13 (1H, d, J=2 Hz, ArH), 7.52 (3H, m, ArH), 7.24 (3H, m,ArH), 5.48 (2H, s, CH₂N), 3.12 (2H, t, J=7 Hz, CH₂CO), 2.57 (2H, t, J=7Hz, CH₂CO).

EXAMPLE 214-[5-Chloro-1-(4-dibenzofuran-4-yl)-1H-indol-3-yl]-4-oxo-butyric acid 1.Methyl-4-[5-chloro-1-(4-dibenzofuran-4-yl)-1H-indol-3-yl]-4-oxo-butyrate

A solution of dibenzofuran-4-boronic acid (144 mg, 0.68 mmol) inmethanol (5 mL) was added to a stirred solution ofmethyl-4-(1-(4-bromobenzyl)-5-chloro-1H-indol-3-yl]-4-oxo-butyrate (250mg, 0.57 mmol) and tetrakis-(triphenylphosphine)palladium(0) (33 mg, 5mol%) in toluene (20 mL). 2N sodium carbonate (0.6 mL, 1.2 mmol) wasadded and the reaction was heated to 90° C. (oil bath temp.) for 2-3 hrsuntil complete (TLC control). The reaction mixture was cooled to roomtemperature and partitioned between water and diethyl ether. The phaseswere separated, the aqueous phase being further extracted with diethylether (2×20 mL). The combined extract was washed with water and brine.The ethereal solution was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to yieldmethyl-4-[5-chloro-1-(4-dibenzofuran-4-yl)-1H-indol-3-yl]-4-oxo-butyrateas a white solid (253 mg, 85%); Rf: 0.3 (30% ethyl acetate in heptane);1H NMR (CDCl₃, 300 MHz) δ 8.40 (1H, s, ArH), 7.95 (4H, m, ArH), 7.58(2H, m, ArH), 7.42 (4H, m, ArH), 7.06-7.38 (6H, m, ArH), 5.42 (2H, s,CH₂N), 3.72 (3H, s), 3.12 (2H, t, J=7 Hz, CH₂CO), 2.77 (2H, t, J=7 Hz,CH₂CO).

2. 4-[5-chloro-1-(4-dibenzofuran-4-yl)-1H-indol-3-yl]-4-oxo-butyric acid

2N Sodium hydroxide solution (0.75 mL, 1.50 mmol) was added dropwise toa stirred solution ofmethyl-4-[5-chloro-1-(4-dibenzofuran-4-yl)-1H-indol-3-yl]-4-oxo-butyrate(253 mg, 0.48 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). Theclear reaction mixture was stirred at room temperature until thereaction was complete (TLC control), and then diluted with water (10mL), and acidified to pH 3 with 2N hydrochloric acid. The reactionmixture was extracted with ethyl acetate (2×20 mL). The combined extractwas washed with water, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification of the product by flash columnchromatography, using 5% methanol in methylene chloride as eluent,afforded the title compound as a white solid (241 mg, 95%): Rf: 0.35 (5%methanol in dichloromethane); 1H NMR (THF-d8, 300 MHz) δ 8.37 (1H, d,J=2 Hz, ArH), 8.32 (1H, s, ArH), 8.02 (1H, d, J=8 Hz, ArH), 7.97 (1H, d,J=8 Hz, ArH), 7.87 (2H, d, J=8 Hz, ArH), 7.58 (2H, m, ArH), 7.32-7.46(6H, m, ArH), 7.15 (1H, d, J=8 Hz, ArH), 5.52 (2H, s, CH₂N), 3.20 (2H,t, J=7 Hz, CH₂CO), 2.67 (2H, t, J=7 Hz, CH₂CO); ESI-LCMS e/z calculatedfor C₃₁H₂₂ClNO₄ 507.971, found 508 [M+H (³⁵Cl)]⁺, 510 [M+H (³⁷Cl)]⁺, 530(M+Na (³⁵Cl)]⁺, 532 [M+Na (³⁷Cl)]⁺.

EXAMPLE 224-[5-Chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyricacid 1.Methyl-4-[5-Chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrate

A solution of methyl-(5-chloro-1H-indol-3-yl)-4-oxo-butyrate (520 mg,1.96 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise to astirred slurry of sodium hydride (95%, 55 mg, 2.16 mmol) intetrahydrofuran (10 mL). After 30 mins, a solution of2-chloro-5-(chloromethyl)pyridine (350 mg, 2.16 mmol) in tetrahydrofuran(10 mL) was added, and the resultant solution was stirred for 2 hours at50° C., cooled to room temperature and then poured carefully into water(20 mL), acidified to pH 4 with 0.5N hydrochloric acid and extractedwith ethyl acetate (3×25 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification by flash column chromatography (50% ethyl acetate inheptane) afforded the methyl ester,methyl-4-[5-chloro-1-(6-chloropyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrateas a colorless oil (667 mg, 87%).

A solution of dibenzofuran-4-boronic acid (422 mg, 1.98 mmol) inmethanol (10 mL) was added to a stirred solutionmethyl-4-[5-chloro-1-(6-chloropyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrate(650 mg, 1.66 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (72mg, 5 mol %) in toluene (40 mL). 2N sodium carbonate (1.66 mL, 3.32mmol) was added and the reaction was heated to 90° C. (oil bath temp.)for 2-3 hrs until complete (TLC control). The reaction mixture wascooled to room temperature and partitioned between water and diethylether. The phases were separated, the aqueous phase being furtherextracted with diethyl ether (2×30 mL). The combined extract was washedwith water and brine. The ethereal solution was dried over anhydrousMgSO₄, filtered and concentrated in vacuo to yieldmethyl-4-[5-chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrateas a white solid (713 mg, 82%); Rf: 0.5 (50% ethyl acetate in heptane);¹H NMR (CDCl₃, 300 MHz) δ 8.71 (1H, s, ArH), 8.41 (2H, m, ArH), 8.27(1H, d, J=8 Hz, ArH), 8.00 (2H, m, ArH), 7.89 (2H, s, ArH), 7.44-7.58(4H, m, ArH), 7.39 (2H, m, ArH), 5.43 (2H, s, CH₂N), 3.71 (3H, s OMe),3.21 (2H, t, J=7 Hz, CH₂CO), 2.80 (2H, t, J=7 Hz, CH₂CO); ESI-LCMS e/zcalculated for C₃₁H₂₃ClN₂O₄ 522.980, found 523 [M+H (³⁵Cl)]⁺, 525 [M+H(³⁷Cl)]⁺, 545 [M+Na (³⁵Cl)]⁺, 547 [M+Na (³⁷Cl)]⁺.

EXAMPLE 234-[5-Chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyricacid

2N Sodium hydroxide solution (1.45 mL, 2.9 mmol) was added dropwise to astirred solution ofmethyl-4-[5-chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrate(500 mg, 0.95 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). Theclear reaction mixture was stirred at room temperature until thereaction was complete (TLC control), and then diluted with water (10mL), and acidified to pH 3 with 2N hydrochloric acid. The reactionmixture was extracted with ethyl acetate (2×20 mL). The combined extractwas washed with water, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification of the product by flash columnchromatography, using 5% methanol in methylene chloride as eluent,afforded the title compound as a white solid (475 mg, 98%): Rf: 0.35(10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.82 (1H,d, J=2 Hz, ArH), 8.76 (1H, s, ArH), 8.31 (1H, d, J=8 Hz, ArH), 8.18 (4H,m, ArH), 7.88 (1H, dd, J=8, 2 Hz, ArH), 7.72 (2H, d, J=9 Hz, ArH), 7.50(2H, q, J=6 Hz, ArH), 7.40 (1H, t, J=7 Hz, ArH), 7.27 (1H, dd, J=8, 2Hz, ArH), 5.65 (2H, s, CH₂N), 3.16 (2H, t, J=7 Hz, CH₂CO), 2.59 (2H, t,J=7 Hz, CH₂CO); ESI-LCMS e/z calculated for C₃₀H₂₁ClN₂O₄ 508.950, found509 [M+H (³⁵Cl)]⁺, 511 [M+H (³⁷Cl)]^(+, 531) [M+Na (³⁵Cl)]⁺, 533 [M+Na(³⁷Cl)]⁺.

EXAMPLE 244-[5-Chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyricacid 1. Ethyl-2,6-diphenyl-isonicotinate

A solution of phenylboronic acid (915 mg, 7.50 mmol) in methanol (15 mL)was added to a stirred solution of ethyl-2,6-dichloro-isonicotinate (750mg, 3.41 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (197 mg, 5mol%) in toluene (60 mL). 2N sodium carbonate (3.41 mL, 6.82 mmol) wasadded and the reaction was heated to 90° C. (oil bath temp.) for 2-3 hrsuntil complete (TLC control). The reaction mixture was cooled to roomtemperature and partitioned between water and diethyl ether. The phaseswere separated, the aqueous phase being further extracted with diethylether (3×30 mL). The combined extract was washed with water and brine.The ethereal solution was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to yield the title compound as a white solid (941mg, 91%); Rf: 0.5 (30% ethyl acetate in heptane); 1H NMR (CDCl₃, 300MHz) δ 8.18 (2H, s, ArH), 8.12 (4H, m, ArH), 7.42 (6H, m, ArH), 4.38(2H, q, J=7 Hz, CH20), 1.39 (2H, t, J=7Hz, CH₃)

2. 4-Bromomethyl-2,6-diphenylpyridine

A solution of ethyl-2,6-diphenyl-isonicotinate (930 mg, 3.06 mmol) inanhydrous tetrahydrofuran (10 mL) was added dropwise to a stirred slurryof lithium aluminium hydride (116 mg, 3.06 mmol) in tetrahydrofuran (20mL) at 0° C. The reaction was stirred at 0° C. for 1 hour and thenquenched by the addition of water (0.12 mL), 2N sodium hydroxide (0.12mL) and finally water (0.36 mL). Celite was added and the reaction wasdiluted with diethyl ether (50 mL), stirred for 10 mins, and filtered.The ethereal solution was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to yield the primary alcohol as a white solid (782mg, 98%).

Dibromotriphenylphosphorane (1.40 g, 3.24 mmol) was added as a solid toa solution of the alcohol (prepared in the previous reduction step) (775mg, 2.95 mmol) in anhydrous dichloromethabe (40 mL). The reaction wasstirred at room temperature for 4 hours and then partitioned betweenwater and diethyl ether. The phases were separated, the aqueous phasebeing further extracted with diethyl ether (3×30 mL). The combinedextract was washed with water and brine. The ethereal solution was driedover anhydrous MgSO₄, filtered and concentrated in vacuo to yield thetitle compound as a white solid (874 mg, 92%); Rf: 0.8 (30% ethylacetate in heptane); 1H NMR (CDCl₃, 300 MHz) δ 8.16 (2H, s, ArH), 8.12(2H, s, ArH), 7.68 (2H, s, ArH), 7.48 (6H, m, ArH), 4.52 (2H, s, CH₂Br).

3.Methyl-4-[5-chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyrate

A solution of methyl-(5-chloro-1H-indol-3-yl)-4-oxo-butyrate (260 mg,0.98 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise to astirred slurry of sodium hydride (95%, 28 mg, 1.03 mmol) intetrahydrofuran (10 mL). After 30 mins, a solution of4-bromomethyl-2,6-diphenylpyridine (334 mg, 1.03 mmol) intetrahydrofuran (10 mL) was added, and the resultant solution wasstirred for 2 hours at 50° C., cooled to room temperature and thenpoured carefully into water (20 mL), acidified to pH 4 with 0.5Nhydrochloric acid and extracted with ethyl acetate (3×25 mL). Thecombined extract was washed with water, brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Purification by flash columnchromatography (50% ethyl acetate in heptane) afforded the methyl ester,methyl-4-[5-chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyrateas a colorless oil (449 mg, 90%); Rf: 0.4 (50% ethyl acetate inheptane); 1H NMR (CDCl₃, 300 MHz) δ 8.42 (1H, s, ArH), 8.04 (4H, m,ArH), 7.89 (1H, s, ArH), 7.42 (6H, m, ArH), 7.20 (4H, m, ArH), 5.41 (2H,s, CH₂N), 3.68 (3H, s OMe), 3.21 (2H, t, J=7 Hz, CH₂CO), 2.78 (2H, t,J=7 Hz, CH₂CO) ; C₃₁H₂₅ClN₂O₃ 509.003, found 509 [M+H (³⁵Cl)]⁺, 531[M+Na (³⁵Cl)]⁺.

4.4-[5-chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyricacid

2N Sodium hydroxide solution (1.45 mL, 2.9 mmol) was added dropwise to astirred solution ofmethyl-4-[5-chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyrate(254 mg, 0.5 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). Theclear reaction mixture was stirred at room temperature until thereaction was complete (TLC control), and then diluted with water (10mL), and acidified to pH 3 with 2N hydrochloric acid. The reactionmixture was extracted with ethyl acetate (2×20 mL). The combined extractwas washed with water, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification of the product by flash columnchromatography, using 5-10% methanol in methylene chloride as eluent,afforded the title compound as a white solid (240 mg, 98%): Rf: 0.45(10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 12.09(1H, s, COOH), 8.80 (1H, s, ArH), 8.15 (1H, d, J=2 Hz, ArH), 8.09 (4H,m, ArH), 7.83 (2H, s, ArH), 7.69 (1H, d, J=8 Hz, ArH), 7.46 (6H, m,ArH), 7.24 (1H, dd, J=8, 2 Hz, ArH), 5.66 (2H, s, CH₂N), 3.17 (2H, t,J=7 Hz, CH₂CO), 2.59 (2H, t, J=7 Hz, CH₂CO); ESI-LCMS e/z calculated forC₃₀H₂₃ClN₂O₃ 494.976, found 495 [M+H (³⁵Cl)]⁺, 497 [M+H (³⁷Cl)]⁺, 517[M+Na (³⁵Cl)]⁺, 519 [M+Na (³⁷Cl)]⁺.

EXAMPLE 25 1-(4-Bromophenyl)-1H-indole

A solution of 1H-indole (3.0 g, 25.6 mmol), 4-fluorobromobenzene (4.48g, 25.6 mmol), potassium fluoride (40% wt on alumina; 3.0 g) and18-crown-6 (690 mg, 2.56 mmol) in anhydrous DMSO (30 mL) was heated at150° C. for 24 hours, and then cooled to room temperature. The reactionmixture was poured into water (50 mL) and extracted with diethyl ether(3×50 mL). The combined organic extract was washed with water (2×30 mL),brine (3×30 mL), dried over anhydrous MgSO₄, filtered and concentratedin vacuo. Purification of the product by flash column chromatography,using 20% ethyl acetate/hexane as eluent, afforded the title compoundhas a pale yellow solid (5.5 g, 76%).

EXAMPLE 26 4′-Indol-1-yl-biphenyl-4-carbaldehyde

To a stirred solution of the bromide (from the previous example) (7.77g, 28.6 mmol) and tetrakis-(triphenylphosphine)palladium(0) (1.8 g, 1.45mmol) in toluene (100 mL) was added a solution of 4-formylphenylboronicacid (5.21 g, 34.5 mmol) in ethanol (20 mL) and 2N sodium carbonate(28.6 mL, 57.2 mmol). The resulting suspension was stirred at 90° C. for4 hrs (TLC control). The reaction was cooled, diluted with water (50 mL)and extracted with diethyl ether (3×100 mL). The combined extract waswashed with water, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The resulting brown solid was redissolved intetrahydrofuran (50 mL). 2N Hydrochloric acid (10 mL) was added and theresulting solution was stirred at room temperature for 1 hour, and thendiluted with water (50 mL) and extracted with diethyl ether (3×100 mL).The combined extract was washed with water, brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Purification of the productby flash column chromatography, using 20% ethyl acetate in heptane aseluent, afforded the title compound as a white solid (8.02 g, 94%), 1HNMR (CDCl₃, 300 MHz) δ 10.1 (1H, s, CHO), 8.01 (2H, d, J=8 Hz, Ar—H),7.70 (5H, m, Ar—H), 7.62 (2H, d, J=8 Hz, Ar—H), 7.39 (1H, d, J=3.5 Hz,Ar—H), 7.22 (3H, m, Ar—H), 6.74 (1H, d, J=3.5 Hz, Ar—H).

EXAMPLE 27 2-(4′-Indol-1-yl-biphen-4-yl)thiazolidine-4-carboxylic acid

A solution of 4′-Indol-1-yl-biphenyl-4-carbaldehyde (500 mg, 1.68 mmol)and L-cysteine (150 mg, 1.26 mmol) in ethanol (5 mL) and dioxan (5 mL)was stirred at 50° C. for 16 hours, cooled to room temperature andconcentrated in vacuo. Trituration with diethyl ether gave the titlecompound as a beige solid (302 mg, 45%): mp. 135-137° C. (dec) . Rf 0.10(20% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz) δ 7.82 (4H,m, Ar—H), 7.65 (6H, m, Ar—H), 7.52 (1H, d, J=8 Hz, Ar—H), 7.10-7.24 (2H,m, Ar—H), 6.74 (1H, s, Ar—H), 5.77 and 5.58 (both 0.5H, s, H-2, 1:1diastereomers), 4.21 and 3.92 (both 0.5H, m, H-4, 1:1 diastereomers),3.10-3.38 (2H, m, 2×H-5) ; ESI-LCMS e/z calcd for C₂₄H₂₀N₂O₂S: 400.500,found 401 (M+H)⁺.

EXAMPLE 28 4-(4-Bromobenzyl)-piperazine-1,2-dicarboxylic acid,1-tert-butyl ester, 2-methyl ester

Piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester, 2-methyl ester(250 mg, 1.03 mmol) was added dropwise to a stirred suspension of4-bromobenzyl bromide (283 mg, 1.14 mmol) and cesium carbonate (1.0 g,3.09 mmol) in anhydrous DMF (10 mL) at room temperature. The reactionmixture was stirred at 40° C. for 3 hrs (TLC control) and then pouredinto water (25 mL) and extracted with diethyl ether (3×25 mL). Thecombined extract was washed with water (2×10 mL), brine (3×10 mL), driedover anhydrous MgSO₄, filtered and concentrated in vacuo. Purificationof the product by flash column chromatography, using 40% ethylacetate/hexane as eluent, afforded the title compound as a white foam(270 mg, 64%).

EXAMPLE 29 4-(4-Bromobenzoyl)-piperazine-1,2-dicarboxylic acid,1-tert-butyl ester, 2-methyl ester

Piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester, 2-methyl ester(250 mg, 1.03 mmol) was added dropwise to a stirred solution of4-bromobenzoyl chloride (250 mg, 1.14 mmol), triethylamine (0.43 mL,3.09 mmol) and DMAP (5 mg) in anhydrous 1,2-dichloroethane (10 mL) atroom temperature. The reaction mixture was stirred for 2 hrs (TLCcontrol) and then poured into water (25 mL) and extracted with diethylether (3×25 mL). The combined extract was washed with water (2×10 mL),brine (3×10 mL), dried over anhydrous MgSO₄, filtered and concentratedin vacuo. Purification of the product by flash column chromatography,using 40% ethyl acetate/hexane as eluent, afforded the title compound asa white foam (310 mg, 71%).

EXAMPLE 30 4-(4-Bromobenesulfonyl)-piperazine-1,2-dicarboxylic acid,1-tert-butyl ester, 2-methyl ester

Piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester, 2-methyl ester(250 mg, 1.03 mmol) was added dropwise to a stirred solution of4-bromobenzenesulfonyl chloride (290 mg, 1.14 mmol) and pyridine (1 mL)in anhydrous 1,2-dichloroethane (10 mL) at room temperature. Thereaction mixture was stirred for 1 hr (TLC control) and then poured intowater (25 mL) and extracted with diethyl ether (3×25 mL). The combinedextract was washed with water (2×10 mL), brine (3×10 mL), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification of theproduct by flash column chromatography, using 40% ethyl acetate/hexaneas eluent, afforded the title compound as a white foam (350 mg, 74%).

EXAMPLE 31

Suzuki Coupling: General methods.

General Method A:

A solution of 4-(dibenzofuran-4-yl)phenyl boronic acid (5.0 mmol) inmethanol (10 mL) was added to a stirred solution of the required arylbromide (4.0 mmol) and tetrakis-(triphenylphosphine)palladium(0) (5 mol%) in toluene (40 mL). 2N sodium carbonate (4 mL, 8.0 mmol) was addedand then the reaction was heated to 80° C. (oil bath temp.) for 2-3 hrsuntil complete (TLC control). The reaction mixture was cooled to roomtemperature and partitioned between water (30 mL) and diethyl ether (50mL). The phases were separated, the aqueous phase being furtherextracted with diethyl ether (2×30 mL). The combined organic extract waswashed with water and brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to yield the coupled product. Purification of theproduct by flash column chromatography, using 20-50% ethylacetate/hexane as eluent, afforded the corresponding methyl ester of thetitle compound.

2N Sodium hydroxide (1.0 mL) was added to a stirred solution of theamido methyl ester in a mixture of tetrahydrofuran (10 mL) and methanol(2 mL). The solution was stirred for 1 hour and then acidified to pH 3with 2N hydrochloric acid. The reaction mixture was extracted with ethylacetate (3×20 mL). The combined extract was washed with water, brine,dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the product by flash column chromatography, using 5-20%methanol in methylene chloride as eluent, afforded the title compound.

General Method B:

A suspension of the required aryl bromide (1 mmol),4-(dibenzofuran-4-yl)phenyl boronic acid (1.2 mmol), cesium carbonate(3. 0 mmol),[1.1′-bis-(diphenylphodphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (3 mol %) and 1.1′-bis-(diphenylphodphino)ferrocene(3 mol %) in anhydrous dioxan (20 mL) was heated at reflux for 4-6 hrs(TLC control). Upon reaction completion, the reaction mixture was cooledto room temperature, poured into water (25 mL) and extracted withdiethyl ether (3×30 mL). The combined organic extract was washed withwater and brine, dried over anhydrous MgSO₄, filtered and concentratedin vacuo to yield the coupled product. Purification of the product byflash column chromatography, using 20-50% ethyl acetate/hexane aseluent, afforded the corresponding methyl ester of the title compound.

2N Sodium hydroxide (1.0 mL) was added to a stirred solution of theamido methyl ester in a mixture of tetrahydrofuran (10 mL) and methanol(2 mL). The solution was stirred for 1 hour and then acidified to pH 3with 2N hydrochloric acid. The reaction mixture was extracted with ethylacetate (3×20 mL). The combined extract was washed with water, brine,dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the product by flash column chromatography, using 5-20%methanol in methylene chloride as eluent, afforded the title compound.

EXAMPLE 324-(4′-Dibenzofuran-4-ylbiphen-4-yl-methyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester

4-(4′-Dibenzofuran-4-ylbiphen-4-ylmethyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester was prepared according to the method describedin Suzuki Coupling Method B, using4-(4-bromobenzyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester,2-methyl ester as the required aryl bromide. The title compound wasisolated as a white solid: Rf: 0.60 (10% methanol in dichloromethane);¹H NMR (DMSO-d6, 300 MHz): δ 8.19 (1H, d, J=9 Hz, Ar—H), 8.15 (1H, d,J=9 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H),7.72 (4H, m, Ar—H), 7.52 (2H, q, J=8 Hz, Ar—H), 7.42 (3H, m, Ar—H), 4.42(1H, m, CHN), 3.60 (2H, m), 3.20 (2H, m), 3.08 (1H, m), 2.82 (1H, m),2.10 (2H, m), 1.40 (9H, s, CMe₃); ESI-LCMS e/z calcd for C₃₅H₃₄N₂O₅562.663, found 563 (M+H)⁺.

EXAMPLE 334-(4′-Dibenzofuran-4-ylbiphen-4-ylmethyl)-piperazine-2-carboxylic acid

Trifluoroacetic acid (0.5 mL) was added to a solution of4-(4′-Dibenzofuran-4-ylbiphen-4-ylmethyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester (80 mg) in anhydrous dichloromethane. Thereaction was stirred at room temperature for 2 hours (TLC control). Theresultant brown oil was reconstituted and concentrated from methanol(3×10 mL) and then from dichloromethane (2×10 mL) to give the titlecompound as a white solid (65 mg, 100%): Rf 0.25 (20% methanol indichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.19 (1H, d, J=9 Hz,Ar—H), 8.16 (1H, d, J=9 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.86 (2H,d, J=9 Hz, Ar—H), 7.72 (4H, m, Ar—H), 7.53 (2H, q, J=8 Hz, Ar—H), 7.45(3H, m, Ar—H), 4.22 (1H, m, CHN), 3.78 (2H, s), 3.35 (1H, m), 3.08 (2H,m), 2.86 (1H, m), 2.58 (2H, m); ESI-LCMS e/z calcd for C₃₀H₂₆N₂O₃462.546, found 563 (M+H)⁺.

EXAMPLE 344-(4′-Dibenzofuran-4-ylbiphenyl-4-carbonyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester

4-(4′-Dibenzofuran-4-ylbiphenyl-4-carbonyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester was prepared according to the method describedin Suzuki Coupling Method B, using4-(4-bromobenzoyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester,2-methyl ester as the required aryl bromide. The title compound wasisolated as a white solid: Rf: 0.30 (10% methanol in dichloromethane);1H NMR (DMSO-d6, 300 MHz): 6 8.18 (2H, t, J=9 Hz, Ar—H), 8.04 (2H, d,J=9 Hz, Ar—H), 7.90 (2H, d, J=9 Hz, Ar—H), 7.82 (2H, d, J=9 Hz, Ar—H),7.75 (2H, dd, J=9, 4 Hz, Ar—H), 7.52 (2H, q, J=8 Hz, Ar—H), 7.45 (3H, m,Ar—H), 4.56 (1H, m, CHN), 3.80 (2H, m), 3.20 (2H, m), 3.14 (2H, m), 1.41(9H, s, CMe₃); ESI-LCMS e/z calcd for C₃₅H₃₂N₂O₆ 576.646, found 577(M+H)⁺, 599 (M+Na)⁺.

EXAMPLE 354-(4′-Dibenzofuran-4-ylbiphenyl-4-carbonyl)-piperazine-2-carboxylic acid

Trifluoroacetic acid (0.5 mL) was added to a solution of4-(4′-Dibenzofuran-4-ylbiphen-4-yl-carbonyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester (135 mg) in anhydrous dichloromethane. Thereaction was stirred at room temperature for 2 hours (TLC control). Theresultant brown oil was reconstituted and concentrated from methanol(3×10 mL) and then from dichloromethane (2×10 mL) to give the titlecompound as a white solid (112 mg, 100%): Rf 0.10 (20% methanol indichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.18 (2H, t, J=9 Hz,Ar—H), 8.04 (2H, d, J=9 Hz, Ar—H), 7.92 (2H, d, J=9 Hz, Ar—H), 7.86 (2H,d, J=9 Hz, Ar—H), 7.75 (2H, t, J=8 Hz, Ar—H), 7.61 (2H, m, Ar—H), 7.53(2H, t, q, J=8 Hz, Ar—H), 7.43 (1H, t, J=8 Hz, Ar—H), 4.34 (1H, m, CHN),3.40 (4H, m), 3.18 (2H, m); ESI-LCMS e/z calcd for C₃₀H₂₄N₂O₄ 476.530,found 477 (M+H)⁺, 499 (M+Na)⁺.

EXAMPLE 364-(4′-Dibenzofuran-4-ylbiphenyl-4-sulfonyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester

4-(4′-Dibenzofuran-4-ylbiphenyl-4-sulfonyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester was prepared according to the method describedin Suzuki Coupling Method B, using4-(4-bromobenesulfonyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butylester, 2-methyl ester as the required aryl bromide. The title compoundwas isolated as a white solid: Rf: 0.60 (10% methanol indichloromethane); ¹H NMR (DMSO-d6, 300 MHz): δ 13.2 (1H, br s, OH), 8.18(2H, t, J=9 Hz, Ar—H), 8.06 (4H, m Ar—H), 7.96 (2H, d, J=9 Hz, Ar—H),7.82 (2H, d, J=9 Hz, Ar—H), 7.75 (2H, t, J=9, 4 Hz, Ar—H), 7.52 (2H, m,Ar—H), 7.44 (1H, t, J=8 Hz, Ar—H), 4.60 (1H, m, CHN), 4.11 (2H, m), 3.82(1H, m), 3.62 (1H, m), 3.06 (1H, m), 2.20 (1H, m), 1.41 (9H, s, CMe₃);ESI-LCMS e/z calcd for C₃₄H₃₂N₂O₇S 612.700, found 635 (M+Na)⁺.

EXAMPLE 374-(4′-Dibenzofuran-4-ylbiphenyl-4-sulfonyl)-piperazine-2-carboxylic acid

Trifluoroacetic acid (0.5 mL) was added to a solution of4-(4′-Dibenzofuran-4-ylbiphen-4-yl-sulfonyl)-piperazine-1,2-dicarboxylicacid, 1-tert-butyl ester (120 mg) in anhydrous dichloromethane. Thereaction was stirred at room temperature for 2 hours (TLC control). Theresultant brown oil was reconstituted and concentrated from methanol(3×10 mL) and then from dichloromethane (2×10 mL) to give the titlecompound as a white solid (101 mg, 100%): Rf 0.10 (20% methanol indichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.19 (2H, t, J=9 Hz,Ar—H), 8.08 (4H, m Ar—H), 7.94 (4H, m, Ar—H), 7.74 (2H, t, J=9, 4 Hz,Ar—H), 7.54 (2H, m, Ar—H), 7.44 (1H, t, J=8 Hz, Ar—H), 4.38 (1H, m,CHN), 3.71 (1H, m), 3.46 (2H, m), 3.19 (1H, m), 2.98 (1H, m), 2.83 (1H,m), 1.41 (9H, s, CMe₃); ESI-LCMS e/z calcd for C₂₉H₂₄N₂O₅S 612.700,found 635 (M+Na)⁺.

EXAMPLE 38(2RS,4R)-2-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-yl]thiazolidine-4-carboxylicacid

A solution of 4′-(2-Benzylbenzofuran-3-yl)biphenyl-4-carbaldehyde (400mg, 1.03 mmol) and L-cysteine (100 mg, 0.83 mmol) in methanol (5 mL) anddioxan (5 mL) was stirred at 40° C. for 16 hours, cooled to roomtemperature and concentrated in vacuo. Trituration with diethyl ethergave the tile compound as an off-white solid (380 mg, 75%): mp. 148° C.(dec) . Rf 0.10 (20% methanol in dichloromethane). 1H NMR (MeOH-d4, 300MHz) δ 7.88 (6H, m, Ar—H), 7.76 (3H, m, Ar—H), 7.52 (1H, d, J=8 Hz,Ar—H), 7.20-7.38 (7H, m, Ar—H), 6.16 and 5.96 (both 0.5H, s, H-2, 1:1diastereomers), 4.98 and 4.78 (both 0.5H, m, H-4, 1:1 diastereomers),3.60-3.90 (2H, m, 2×H-5); ESI-LCMS e/z calcd for C₃₁H₂₅NO₃S 491.608,found 492 (M+H)⁺.

EXAMPLE 39 4-Benzyl-2,6-dichloro-pyrimidine

1.78 g ( 9.70 mmoles) of 2,4,6-Trichloro-pyrimidine was dissolved in 10mls of anhydrous THF and chilled to −78° C. 4.9 mls (9.8 mmoles) ofbenzyl magnesium chloride (2M in THF) was added dropwise and thesolution allowed to warm to ambient temperature. The reaction wasstirred for 3 hours, then quenched with 20 mls of water and extractedthree times with ethyl acetate. The combined organic phases were washedwith saturated NaCl solution, dried over NaSO4 and evaporated underreducd pressure. The crude residue was purified by flash chromatography,using EtOAc/Heptane as the eluent to yield 1.08 g (47%) of4-benzyl-2,6-dichloro-pyrimidine as a light yellow oil. ¹H NMR (CDCl₃03-499-77b)

EXAMPLE 40 (6-Benzyl-2-chloro-pyrimidin-4-ylamino)-acetic acid methylester

1.87 g (7.8 mmole) of 4-benzyl-2,6-dichloro-pyrimidine was dissolved in15 mls of DMF. To this solution was added 1.08 g of glycine methyl esterHCl. Next 3.0 mls of triethyl amine was added dropwise and the reactionstirred was then heated to 70° C. for 3 hours. The reaction was dilutedwith 10 mls of H₂0 and extracted with two portions of EtOAc. Thecombined organic layers were washed with two portions of saturated NaClsolution, dried over MgSO4, filter and evaporated under reduced pressureto yield a crude oil. This material was chromatographed on silica gelwith 10% Ethyl Acetate-90% Heptane as the eluent.(6-Benzyl-2-chloro-pyrimidin-4-ylamino)-acetic acid methyl ester (0.354g, 20%) was isolated a clear oil.

EXAMPLE 416-Benzyl-2-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-acetic acidmethyl ester

0.398 g (1.36mmole) of (6-benzyl-2-chloro-pyrimidin-4-ylamino)-aceticacid methyl ester and 0.404 g (1.4 mmole) of 4-dibenzofuran-4-yl-boronicacid was dissolved in 7 mls toluene-3 mls of EtOH. To this solution wasadded 0.157 g (0.14 mmole) of Pd(PPh3)4, then 0.430 g (4.05 mmole)Na₂CO₃ in 4 mls of H₂O was added to the stirred solution and heated torefluxing for 3 hr. After reaction mixture was cooled down to roomtemperature and then diluted with 50 ml ethyl acetate, Then aqueouslayer was separated, organic layer was washed with sat. NaCl solution,dried with MgSO4, concentrated and then residue was purified by flashcolumn with 10% ethyl acetate in heptane to yield 0.513 g of titlecompound, 75% yield.

EXAMPLE 426-Benzyl-2-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-acetic acid

0.320 g (0.64 mmole) of6-Benzyl-2-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-acetic acidmethyl ester was dissolved in 10 mls THF-1 ml MeOH. To this solution wasadded 3.0 mls of 1M NaOH. The reaction was stirred for 12 hours at roomtemperature before quenched with 10% HC. PH was adjusted to 2 anddiluted with 25 ml of ethyl acetate. After organic layer was separated,aqueous layer was extracted with 15 ml of ethyl acetate. Organic layerwas combined, dried over MgSO4 and concentrated. The residue waspurified by flash column by 2-5% methanol in dichloromethane to yield119 g (60%) title compound as a light yellow solid .MP 172-174° C.,R_(f) 0.46 (20% Methanol-80% Methylene Chloride); ¹H NMR (DMSO-d₆) 12.45(br s, 1H), 8.23-8.16 (m, 4H), 8.03 (d, J=8.1 Hz, 2H), 7.78-7.74 (m,2H), 7.54-7.20 (m, 9H), 4.00 (d, J=4.2 Hz, 2H), 3.94 (s, 2H).

EXAMPLE 43 3-(2-Benzyl-6-chloro-pyrimidin-4-ylamino)-propionic acidmethyl ester

0.503 g (2.1 mmole) of 2-benzyl-4,6-dichloro-pyrimidine was dissolved in10 mls of DMF. To this solution was added 0.340 g of 3-amino-propionicacid methyl ester HCl. Next 0.6 mls of triethyl amine 94.3mmoles) wasadded dropwise and the reaction stirred at room temperature for 12hours. The reaction was diluted with 10 mls of H₂0 and extracted withtwo portions of EtOAc. The combined organic layers were washed with twoportions of saturated NaCl solution, dried over MgSO4, filter andevaporated under reduced pressure to yield a crude oil. This materialwas chromatographed on silica gel with 10% Ethyl Acetate-90% Heptane asthe eluent. 3-(2-benzyl-6-chloro-pyrimidin-4-ylamino)-propionic acidmethyl ester (0.531g, 79%) was isolated a clear oil.

EXAMPLE 443-[2-Benzyl-6-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-propionicacid methyl ester

0.244 g (0.76 mmole) of3-(2-benzyl-6-chloro-pyrimidin-4-ylamino)-propionic acid methyl esterand 0.230 g (0.79 mmole) of 4-dibenzofuran-4-yl-boronic acid wasdissolved in 7 mls toluene-3 mls of EtOH. To this soltion was added0.092 g of Pd(PPh3)4, then 0.258 g (4.05 mmole) Na₂CO₃ in 5 mls of H₂Owas added to the stirred solution and heated to refluxing for 2 hr.After reaction mixture was cooled down to room temperature and thendiluted with 50 ml ethyl acetate. Then aqueous layer was separated,organic layer was washed with sat. NaCl solution, dried with MgSO4,concentrated and then residue was purified by flash column with 10%ethyl acetate in heptane to yield 0.241 g of title compound, 60% yield.

EXAMPLE 453-[2-Benzyl-6-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-propionicacid

Isolated as an off white solid .MP 205° C. decomp, R_(f) 0.61 (20%Methanol-80% Methylene Chloride); ¹H NMR (DMSO-d₆) δ 12.23 (br s, 1H),8.21-8.08 (m, 4H), 8.02 (d, J=8.7 Hz, 2H), 7.76-7.72 (m, 2H), 7.56-7.17(m, 8H), 6.88 (s, 1H), 4.00 (s, 2H), 3.54 (m, 2H), 2.55-2.47 (m, 2Hobscured by DMSO); LCMS m/z calcd for C₃₂H₂₅N₃O₃: 499.56 found 500.3(M+1).

EXAMPLE 463-[2-phenyl-6-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-propionicacid

Isolated as a light yellow solid. MP 210° C. decomp, R_(f) 0.15 (10%Methanol-90% Methylene Chloride); ¹H NMR (DMSO-d₆) 12.50 (br s, 1H),8.49-8.46 (m, 2H), 8.36-8.17 (m, 4H), 8.08 (d, J=8.4 Hz, 2H), 7.77 (d,J=7.5 Hz, 2H), 7.57-7.40 (m, 7H), 7.01 (s, 1H), 3.70 (m, 2H), 4.65 (t,J=6.9 Hz, 2H); LCMS m/z calcd for C₃₁H₂₃N₃O₃: 485.54 found 486.3 (M+1).

EXAMPLE 473-[2-(4-Dibenzofuran-4-yl-phenyl)-6-phenyl-pyrimidin-4-ylamino]-propionicacid

Isolated as a light yellow foam. R_(f) 0.21 (20% Methanol-80% MethyleneChloride); ¹H NMR (DMSO-d₆) 8.62 (d, J=8.7 Hz, 2H), 8.21-8.10 (m, 4H),8.06 (d, J=8.7 Hz, 2H), 7.78 (t, J=8.4 Hz, 2H), 7.56-7.40 (m, 7H), 6.95(s, 1H), 3.72 (s, 2H), 2.66 (t, J=6.6 Hz, 2H), LCMS m/z calcd forC₃₁H₂₃N₃O₃ 485.54 found 486.3 (M+1).

EXAMPLE 48[2-(4-Dibenzofuran-4-yl-phenyl)-6-phenyl-pyrimidin-4-ylamino]-aceticacid

Isolated as a light yellow foam. R_(f) 0.44 (20% Methanol-80% MethyleneChloride); ¹H NMR (DMSO-d₆) 12.60 (br s, 1H), 8.59 (d, J=8.4 Hz, 2H),8.20-8.10 (m, 4H), 8.05 (d, J=8.4 Hz, 2H), 7.86 (m, 1H), 7.77 (t, J=8.1Hz, 2H), 7.56-7.40 (m, 6H), 7.05 (s, 1H), 4.18 (d, J=4.5 Hz, 2H).

EXAMPLE 49

Representative compounds of the invention include

-   -   1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4-(benzyloxy)proline;    -   4-(benzyloxy)-1-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}proline;    -   1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl)sulfonyl}proline;    -   4-(benzyloxy)-1-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)proline;    -   1-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)proline;    -   2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic        acid;    -   1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}piperidine-2-carboxylic        acid;    -   1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}piperidine-3-carboxylic        acid;    -   1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}proline;    -   (2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic        acid;    -   (1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}pyrrolidin-2-yl)acetic        acid;    -   1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl)carbonyl}-3-phenylproline;    -   (4R)-1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-4-(benzyloxy)-L-proline;    -   {1-benzyl-5-[4-(1H-indol-1-yl)phenyl]-1H-indol-3-yl}acetic acid;    -   1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-5-oxoproline;    -   [5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1-(tert-butoxycarbonyl)-1H-indol-3-yl]acetic        acid;    -   {5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1-[(4-methyl-3-nitrophenyl)sulfonyl]-1H-indol-3-yl}acetic        acid;    -   3-{[5-{4-[(2-butyl-1-benzofuran-3-yl)methyl]phenyl}-2-(3-phenylpropoxy)pyridin-3-yl)amino}-3-oxopropanoic        acid;    -   [5-[4-(1H-indol-1-yl)phenyl]-1-(2-naphthylmethyl)-1H-indol-3-yl]acetic        acid;    -   (4R)-2-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-1,3-thiazolidine-4-carboxylic        acid;    -   (4R)-2-[4′-(1H-indol-1-yl)biphenyl-4-yl]-1,3-thiazolidine-4-carboxylic        acid;    -   1-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl)-4-hydroxyproline;    -   {5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}acetic        acid;    -   {5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}acetic        acid;    -   3-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl)-2-phenyl-1H-benzimidazol-1-yl}propanoic        acid;    -   4-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}butanoic        acid;    -   4-{5-(4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}butanoic        acid;    -   4-[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-(2-phenylethyl)-1H-benzimidazol-1-yl]butanoic        acid;    -   4-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}butanoic        acid;    -   3-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}propanoic        acid;    -   3-[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-(2-phenylethyl)-1H-benzimidazol-1-yl]propanoic        acid;    -   {2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}acetic        acid;    -   3-{1-benzyl-5-(4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-2-yl}propanoic        acid;    -   {1-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-2-yl}acetic        acid;    -   2-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}-3-phenylpropanoic        acid;    -   2-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-methyl-1H-benzimidazol-1-yl}-3-phenylpropanoic        acid;    -   2-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl)-1H-benzimidazol-1-yl}-3-phenylpropanoic        acid;    -   [2-benzyl-7-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]acetic        acid;    -   methyl        1-{[4-({(4-(4-chlorophenyl)-5-(4-ethylphenyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl]sulfonyl}prolinate;    -   {3-[4-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl]-1-benzofuran-2-yl}(phenyl)acetic        acid    -   4-(benzyloxy)-1-{[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]carbonyl}-L-proline;    -   {5-[4-(1H-indol-1-yl)phenyl]-1-[(4-methyl-3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-indol-3-yl}acetic        acid;    -   {5-[4-(2-benzyl-1-benzofuran-3-yl}phenyl]-1H-indol-3-yl}acetic        acid;    -   [6-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl]acetic        acid;    -   [4-(4-dibenzo[b,d]thien-4-ylphenyl)piperazin-1-yl](phenyl)acetic        acid;    -   3-{[5-{4-[(2-butyl-1-benzofuran-3-yl)methyl]phenyl}-2-oxo-1-(3-phenylpropyl)-1,2-dihydropyridin-3-yl]amino}-3-oxopropanoic        acid;    -   ({4′-[10-(ethoxycarbonyl)pyrido[1,2-a]indol-3-yl]biphenyl-4-yl}oxy)(phenyl)acetic        acid;    -   N-[5-[4-(2-Butyl-benzofuran-3-ylmethyl)-phenyl]-2-oxo-1-(3-phenyl-propyl)-1,2-dihydro-pyridin-3-yl]-malonamic        acid;    -   N-[1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamic        acid;    -   [5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic        acid;    -   [5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetic        acid;    -   1-{[4-({[4-(4-chlorophenyl)-5-(4-ethylphenyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl]sulfonyl}proline;    -   {[1-benzyl-5-(4-dibenzo[b,d]furan-4-ylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]amino)(oxo)acetic        acid;    -   [5-(4-Dibenzofuran-4-yl-phenyl)-3-phenyl-2,3-dihydro-pyrazol-1-yl]-acetic        acid;    -   [5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-fluoro-phenyl)-pyrazol-1-yl]-acetic        acid;    -   2-{[4-(2-Dibenzofuran-4-yl-thiazol-4-yl)-benzenesulfonyl]-ethyl-amino}-3-phenyl-propionic        acid;    -   N-[5-(4-Dibenzofuran-4-yl-phenyl)-1-(3-fluoro-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamic        acid;    -   [5-(4-Dibenzofuran-4-yl-phenyl)-1-(3-fluoro-benzyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino]-acetic        acid;    -   N-[5-(4-Dibenzofuran-4-yl-phenyl)-2-oxo-1-(3-phenyl-propyl)-1,2-dihydro-pyridin-3-yl]-oxalamic        acid;    -   2-{[2-(4-Dibenzofuran-4-yl-phenyl)-4-trifluoromethyl-pyrimidine-5-carbonyl]-amino}-3-phenyl-propionic        acid;    -   N-[1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-malonamic        acid;    -   2-{[6-(4-Dibenzofuran-4-yl-phenyl)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic        acid;    -   N-[4-Bromo-5-(4-dibenzofuran-4-yl-phenyl)-thiazol-2-yl]-oxalamic        acid;    -   [5-(4-Dibenzofuran-4-yl-phenyl)-6-methyl-pyridin-2-yloxy]-phenyl-acetic        acid;    -   [5-(4-Dibenzofuran-4-yl-phenyl)-indol-1-yl]-phenyl-acetic acid;    -   [6-Benzyl-2-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-acetic        acid;    -   3-[2-Benzyl-6-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-propionic        acid;    -   3-[6-(4-Dibenzofuran-4-yl-phenyl)-2-phenyl-pyrimidin-4-ylamino]-propionic        acid;    -   3-[2-(4-Dibenzofuran-4-yl-phenyl)-6-phenyl-pyrimidin-4-ylamino]-propionic        acid;    -   [2-(4-Dibenzofuran-4-yl-phenyl)-6-phenyl-pyrimidin-4-ylamino]-acetic        acid;    -   4-[1-(2-Biphenyl-4-yl-2-oxo-ethyl)-5-chloro-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-(5-Chloro-1-{2-[4-(2-methoxy-dibenzofuran-3-ylamino)-phenyl]-2-oxo-ethyl}-1H-indol-3-yl)-4-oxo-butyric        acid;    -   4-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethyl)-piperazine-1,2-dicarboxylic        acid 1-tert-butyl ester;    -   4-(4′-Dibenzofuran-4-yl-biphenyl-4-sulfonyl)-piperazine-1,2-dicarboxylic        acid 1-tert-butyl ester;    -   4-[5-Chloro-1-(4-thianthren-1-yl-benzyl)-1H-indol-3-yl)-4-oxo-butyric        acid;    -   4-[5-Chloro-1-(4-dibenzothiophen-4-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   1-(tert-butoxycarbonyl)-4-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)oxy]proline    -   1-(tert-butoxycarbonyl)-4-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)thio)proline    -   1-(tert-butoxycarbonyl)-4-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)sulfinyl]proline    -   1-(tert-butoxycarbonyl)-4-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)sulfonyl]proline    -   1-{4-[4-(4-Chloro-phenyl)-5-(4-ethyl-phenyl)-thiazol-2-ylcarbamoyl]-benzenesulfonyl}-pyrrolidine-2-carboxylic        acid;    -   4-(4′-dibenzofuran-4-yl-bipheny-4-ylsulfnayl)-N-tert-butoxycarbonyl-proline;    -   4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-proline;    -   [[5-(4-Dibenzofuran-4-yl-phenyl)-thiophene-2-sulfonyl]-(3-trifluoromethyl-benzyl)-amino]-acetic        acid;    -   4-[1-(4,6-bis-Dimethylamino-[1,3,5]-triazin-2-yl)-5-bromo-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-{5-Bromo-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-(2,3-dihydro-indol-1-yl)-6-piperidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-(2,3-dihydro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-(5-fluoro-2,3-dihydro-indol-1-yl}-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-(5-fluoro-indol-1-yl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(3,4-dihydro-2H-quinolin-1-yl)-[1,3,5)-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-(5-Chloro-1-[4-(3,4-dihydro-2H-quinolin-1-yl)-6-(4-phenyl-piperazin-1-yl)-[1,3,5]-triazin-2-yl]-1H-indol-3-yl)-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-cyclopentyloxy-6-(3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-(3,4-dihydro-2H-quinolin-1-yl)-6-phenyl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-[5-chloro-1-(4-dibenzofuran-4-yl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-[5-Chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-[5-Chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-[5-Chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyric        acid;    -   2-(4′-Indol-1-yl-biphen-4-yl)thiazolidine-4-carboxylic acid;    -   4-(4-Bromobenzyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl        ester, 2-methyl ester;    -   4-(4-Bromobenzoyl)-piperazine-1,2-dicarboxylic acid,        1-tert-butyl ester, 2-methyl ester;    -   4-(4′-Dibenzofuran-4-ylbiphen-4-yl-methyl)-piperazine-1,2-dicarboxylic        acid, 1-tert-butyl ester;    -   4-(4′-Dibenzofuran-4-ylbiphen-4-ylmethyl)-piperazine-2-carboxylic        acid;    -   4-(4′-Dibenzofuran-4-ylbiphenyl-4-carbonyl)-piperazine-1,2-dicarboxylic        acid, 1-tert-butyl ester;    -   4-(4′-Dibenzofuran-4-ylbiphenyl-4-carbonyl)-piperazine-2-carboxylic        acid;    -   4-(4′-Dibenzofuran-4-ylbiphenyl-4-sulfonyl)-piperazine-1,2-dicarboxylic        acid, 1-tert-butyl ester;    -   4-(4′-Dibenzofuran-4-ylbiphenyl-4-sulfonyl)-piperazine-2-carboxylic        acid;    -   (2RS,4R)-2-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-yl]thiazolidine-4-carboxylic        acid;    -   6-Benzyl-2-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-acetic        acid;    -   3-[2-Benzyl-6-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-propionic        acid methyl ester;    -   3-[2-Benzyl-6-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-propionic        acid;    -   3-[2-phenyl-6-(4-dibenzofuran-4-yl-phenyl)-pyrimidin-4-ylamino]-propionic        acid;    -   3-[2-(4-Dibenzofuran-4-yl-phenyl)-6-phenyl-pyrimidin-4-ylamino]-propionic        acid;    -   [2-(4-Dibenzofuran-4-yl-phenyl)-6-phenyl-pyrimidin-4-ylamino]-acetic        acid;    -   4-{5-Chloro-1-[4-(dibenzofuran-4-ylamino)-benzyl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[4-(2-methoxy-dibenzofuran-3-ylamino)-benzyl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-[5-Chloro-1-(4-thianthren-1-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-[5-Chloro-1-(4-dibenzofuran-4-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-[5-Chloro-1-(4-dibenzothiophen-4-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[2-oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   4-{5-Chloro-1-[2-(5-chloro-3-methyl-benzo[b]thiophen-2-yl)-2-oxo-ethyl]-1H-indol-3-yl}-4-oxo-butyric        acid;    -   and pharmaceutically acceptable salts thereof.

EXAMPLE 50

Method for Measuring PTP-1B Activity

The test compounds are evaluated for their in vitro inhibitory activityagainst recombinant human PTP1B with phosphotyrosyl dodecapeptide TRDI(P) YETD (P)Y (P) YRK. This corresponds to the 1142-1153 insulinreceptor kinase regulatory domain, phosphorylated on the 1146, 1150 and1151 tyrosine residues; IR-triphosphopeptide as a source of substrate.Enzyme reaction progression is monitored via the release of inorganicphosphate as detected by the malachite green—ammonium molybdate methodfor the phosphopeptide.

Preferred compounds of the invention exhibit IC₅₀ values of less than 10μM; more preferred compounds of the invention exhibit IC₅₀ values ofless than 1 μM. Particularly preferred compounds exhibit IC₅₀ values ofless than 300 nM.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the invention and that modifications may be made thereinwithout departing from the spirit or scope of the invention as set forthin the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thisspecification.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein, R₁ is H, C₁-C₆alkyl, phenyl(C₁-C₆)alkyl, or C₃-C₆ alkenyl; L is a bond, —SO₂—, —C(O)—,—O—(C₁-C₆)alkyl-, —(C₁-C₆)alkyl-O—, —C(O)—(C₁-C₆)alkyl-, —(C₁-C₆)alkyl-C(O)—, —O—, —S—, —SO—, —SO₂—, or —(C₁-C₄) alkyl-, L₂ is a bond,—NR₈—, —O—, —S—, —SO—, —SO₂—, —(C₁-C₄)alkyl-, —NR₈C(O)—, or —C(O)NR₈—;L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄) alkyl-, C₂-C₆alkenyl, or C(O); R₂ is H, halogen, arylalkoxy, aryl, arylalkyl,alkoxycarbonyl, C₁-C₆ alkyl optionally substituted with phenyl, C₁-C₆alkoxy optionally substituted with phenyl, —(C₁-C₄) alkyl-C(O)NH₂,—(C₁-C₄) alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄)alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄)alkyl, —SO₂-aryl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄) alkyl-heterocycloalkyl,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or OH, wherein each heterocycloalkylis optionally substituted with a total of 1, 2, 3, or 4 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or —SO₂—(C₁-C₄) alkyl;wherein each aryl group within R₂ is optionally substituted with 1, 2,3, 4, or 5 groups that are independently alkyl, alkoxy, halogen,haloalkyl, haloalkoxy, or NO₂; wherein b is 0, 1, or 2; each R₆ and R₇are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl, alkanoyl,arylalkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, heteroarylcarbonyl,heteroaryl, heterocycloalkylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂—aryl, wherein the cyclic groupsare optionally substituted with 1, 2, 3, or 4 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or haloalkoxy; R₈at each occurrence is independently H or C₁-C₆ alkyl; R₂₀, R₂₁, R₂₂, andR₂₃ are independently selected from H, arylalkoxy, arylalkyl, halogen,alkyl, OH, alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,NH-aryl, NHC(O)—(C₁-C₄) alkyl-aryl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄)alkyl-aryl, N(C₁-C₄)alkyl-aryl, —NHSO₂-aryl, —N(C₁-C₄alkyl)SO₂aryl,wherein the aryl group is optionally substituted with 1, 2, 3, or 4groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH,NO₂, haloalkyl, haloalkoxy; the A ring is aryl, heteroaryl, orheterocycloalkyl, each of which is optionally substituted with 1, 2, or3 groups that are independently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl; the B ring is heterocycloalkyl, orheteroaryl, wherein each is optionally substituted with 1, 2, 3, or 4groups that are independently alkyl, alkoxy, arylalkyl, arylalkoxy,halogen, alkoxycarbonyl, aryl, or OH; Q is H, aryl, -aryl-carbonyl-aryl,-aryl-alkyl-aryl, -aryl-alkyl-heteroaryl, -aryl-heteroaryl,-heteroaryl-aryl, -aryl-heterocycloalkyl, heteroaryl,-heteroaryl-alkyl-aryl, or -heterocycloalkyl, wherein the aforementionedcyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl; Y is selected from abond, —O—(C₁-C₆ alkyl)- optionally substituted with phenyl,—NHC(O)—(C₁-C₄)alkyl-, —N(C₁-C₄) alkylC(O)—(C₁-C₄) alkyl-, —(C₁-C₄)alkyl- optionally substituted with phenyl, —N(R₈)C₁-C₆ alkyl-,—C(O)—C₁-C₆ alkyl, —C₁-C₆ alkyl-C(O)—, —C(O)NR₈—, —C(O)N(R₈)—C₁-C₆alkyl, wherein the alkyl portion is optionally substituted with phenyl,—C(O)NR₈, —NR₈C(O)—, —C₁-C₆ alkyl-NR₈—, —SO₂N(R₉₀)—C₁-C₄ alkyl-, or—NR₈C(O)—; wherein R₉₀ is H, C₁-C₆ alkyl, phenyl, or —C1-C4alkyl-phenyl, wherein the phenyl groups are optionally substituted with1, 2 3, 4, or 5 groups that are independently alkyl, alkoxy, halogen,haloalkyl, CN, or haloalkyl, and Z is absent or phenyl optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, or hydroxy.
 2. A compound according toclaim 1, wherein R₁ is H, C₁-C₆ alkyl, benzyl, or allyl; L₃ is a bond,—(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄) alkyl-, or C(O); R₂ isphenyl C₁-C₄ alkoxy, phenyl, naphthyl, phenyl C₁-C₄ alkyl, naphthylC₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —(C₁-C₄)alkyl-C(O)NH₂, —(C₁-C₄) alkyl-C(O)NH (C₁-C₄) alkyl, —(C₁-C₄) alkyl-C(O)N(C₁-C₄) alkyl(C₁-C₄)alkyl, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl,—SO₂-phenyl, —SO₂-naphthyl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄)alkyl-piperidinyl, —(C₁-C₄) alkyl-pyrrolidinyl, -—C₁-C₄)alkyl-morpholinyl, or OH, wherein the piperidinyl, pyrrolidinyl andmorpholinyl rings are optionally substituted with 1, 2, 3, or 4 groupsthat are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or—SO₂—(C₁-C₄) alkyl; wherein the phenyl and naphthyl groups areoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or NO₂; wherein b is 0, 1, or 2; R₈ is H or C₁-C₆ alkyl;R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H, phenyl C₁-C₆alkoxy, phenyl C₁-C₆ alkyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂,NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl,NHC(O)—(C₁-C₄) alkyl-phenyl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄) alkyl-phenyl,N(C₁-C₄)alkyl-phenyl, —NHSO₂-phenyl, —N(C₁-C₄alkyl)SO₂phenyl, whereinthe phenyl group is optionally substituted with 1, 2, 3, or 4 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy; the A ring is phenyl, indolyl,benzofuranyl, dibenzofuranyl, dibenzothienyl, thianthrenyl, thiazolyl,or isoindolyl, each of which is optionally substituted with 1, 2, or 3groups that are independently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N (C₁-C₆) alkyl(C₁-C₆) alkyl; the B ring is pyrrolidinyl, tetrahydroisoquinolinyl,piperidinyl, piperazinyl, pyrrolidinonyl, pyrrolyl, thienyl, thiazolyl,pyrazolyl, thiazolidinyl, dihydroquinoxalinonyl, pyridinonyl,dihydroisoquinolinyl, indolyl, benzimidazolyl, quinolinyl, pyridinyl, orpyrimidinyl, wherein each is optionally substituted with 1, 2, 3, or 4groups that are independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl,phenyl (C₁-C₄) alkoxy (benzyloxy), halogen, C₁-C₆ alkoxycarbonyl,phenyl, or OH; Q is H, phenyl, -phenyl-carbonyl-phenyl,-phenyl-alkyl-phenyl, -phenyl-alkyl-benzofuranyl, -phenyl-pyridyl,-phenyl-benzofuranyl, -phenyl-piperidinyl, -phenyl-pyrrolidinyl,indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl,-pyridyl-phenyl, -pyrimidyl-phenyl, -benzofuranyl-C₁-C₄ alkyl-phenyl,-pyridyl-C₁-C₄ alkyl-phenyl, -piperidinyl, pyrrolidinyl, or indolinyl,wherein each aforementioned cyclic group is optionally substituted with1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkoxycarbonyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,NR₆R₇, or phenyl; Y is selected from a bond, —NHC(O)—(C₁-C₄) alkyl-,—N(C₁-C₄) alkyl-C(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl- wherein the alkylis optionally substituted with phenyl, —SO₂N(R₈)—C₁-C₆ alkyl-, —C₁-C₆alkyl-SO₂N(R₈), —N(R₈)SO₂N(R₈)—C₁-C₆ alkyl-, —C₁-C₆ alkyl-N(R₈)SO₂—,—C(O)NR₈—, or —NR₈C(O)—; and Z is absent or phenyl optionallysubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, or hydroxy.
 3. A compound according toclaim 2, wherein R₂₂ and R₂₃ are both H; R₂ is benzyloxy, phenethyloxy,phenyl, phenyl C₁-C₄ alkyl, —CH₂-naphthyl, C₁-C₆ alkoxycarbonyl, C₁-C₆alkyl, C₁-C₆ alkoxy, —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄)alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄) alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl,—(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl, —SO₂-phenyl, (C₁-C₄)hydroxyalkyl, —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄) alkyl-pyrrolidinyl,—(C₁-C₄) alkyl-morpholinyl, or OH, wherein the piperidinyl, pyrrolidinyland morpholinyl groups are optionally substituted with 1, 2, or 3 groupsthat are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or—SO₂—(C₁-C₄) alkyl; wherein the phenyl and naphthyl groups areoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or NO₂; each R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₆)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₆)alkoxycarbonyl, pyridylcarbonyl,pyridyl, piperidinyl, morpholinyl, pyrrolidinylcarbonyl, —C(O)NH₂,—C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-phenyl,wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂,OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄ haloalkyl orC₁-C₄ haloalkoxy, wherein b is 0, 1, or 2; and Z is absent.
 4. Acompound according to claim 3 of the formula

wherein the B ring is pyrrolidinyl, tetrahydroisoquinolinyl,piperidinyl, piperazinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl,thiazolidinyl, dihydroquinoxalinonyl, pyridinonyl, ordihydroisoquinolinyl, wherein each is optionally substituted with 1, 2,3, or 4 groups that are independently alkyl, alkoxy, phenyl (C₁-C₄)alkyl (benzyl), phenyl (C₁-C₄) alkoxy (benzyloxy), halogen, C₁-C₆alkoxycarbonyl, phenyl, or OH; Q is H, phenyl, -phenyl-alkyl-phenyl,-phenyl-pyridyl, -phenyl-benzofuranyl, -phenyl-piperidinyl,-phenyl-pyrrolidinyl, indolizinyl, benzofuranyl, indolyl, isoindolyl,quinolinyl, -pyridyl-phenyl, -benzofuranyl-C₁-C₄ alkyl-phenyl,-pyridyl-C₁-C₄ alkyl-phenyl, -piperidinyl, -pyrrolidinyl, -indolinyl,wherein the aforementioned cyclic groups are optionally substituted with1, 2, 3, 4, or 5 groups that are independently alkoxycarbonyl, C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NR₆R₇,or phenyl; wherein each R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₄)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl,(C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl, pyridylcarbonyl, or—SO₂-phenyl, wherein the cyclic groups are optionally substituted with1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄haloalkyl or C₁-C₄ haloalkoxy; and Y is selected from a bond,—NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄) alkylC(O)—(C₁-C₄) alkyl-, —(C₁-C₄)alkyl- wherein the alkyl is optionally substituted with phenyl, or—NHC(O)—.
 5. A compound according to claim 4, wherein R₁ is H or C₁-C₄alkyl; and R₂ is benzyloxy, phenethyloxy, phenyl, phenyl C₁-C₄ alkyl,—CH₂-naphthyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —(C₁-C₄)alkyl-S(O)₂—(C₁-C₄) alkyl, —SO₂-phenyl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄)alkyl-piperidinyl, —(C₁-C₄) alkyl-pyrrolidinyl, —(C₁-C₄)alkyl-morpholinyl, or OH, wherein the piperidinyl, pyrrolidinyl andmorpholinyl groups are optionally substituted with a total of 1, 2, or 3groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or—SO₂—(C₁-C₄) alkyl; wherein the phenyl and naphthyl groups areoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or NO₂.
 6. A compound according to claim 5, wherein R₂₀, andR₂₁ are independently selected from H, benzyloxy, benzyl, halogen, C₁-C₆alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl, N(C₁-C₄)alkyl-phenyl, wherein thephenyl group is optionally substituted with 1, 2, 3, or 4 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy; and the B ring is pyrrolidinyl,tetrahydroisoquinolinyl, piperidinyl, pyrrolidinonyl, thiazolidinyl,pyrrolyl, pyrazolyl, dihydroquinoxalinonyl, pyridinonyl, wherein each isoptionally substituted with 1, 2, 3, or 4 groups that are independentlyalkyl, alkoxy, benzyl, benzyloxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl,OH.
 7. A compound according to claim 6, wherein Q is H, phenyl,-phenyl-carbonyl-phenyl, -phenyl-C₁-C₂ alkyl-phenyl, -phenyl-pyridyl,-phenyl-benzofuranyl, indolizinyl, benzofuranyl, indolyl, isoindolyl,quinolinyl, -benzofuranyl-C₁-C₄ alkyl-phenyl, -pyridyl-C₁-C₄alkyl-phenyl, -piperidinyl, -pyrrolidinyl, -indolinyl, wherein theaforementioned cyclic groups are optionally substituted with 1, 2, 3, 4,or 5 groups that are independently CL-C₆ alkoxycarbonyl, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, CF₃, OCF₃, NR₆R₇, or phenyl; wherein R₆ and R₇are independently H, C₁-C₆ alkyl, benzyl, C₂-C₆ alkanoyl,phenyl(C₁-C₄)alkanoyl, (C₁-C₆)alkoxycarbonyl,phenyl(C₁-C₄)alkoxycarbonyl, or —SO₂-phenyl, wherein the cyclic groupsare optionally substituted with 1, 2, 3, or 4 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄ haloalkyl or C₁-C₄haloalkoxy.
 8. A compound according to claim 7, of the formula

wherein L₃ is a bond, or —(C₁-C₄) alkyl-; R₁ is H or C₁-C₄ alkyl; R₂ isbenzyloxy, phenyl, phenyl C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆alkyl, C₁-C₆ alkoxy, —SO₂-phenyl, (C₁-C₄) hydroxyalkyl or OH, whereinthe phenyl group is optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, or NO₂. R₂₀, and R₂₁ are independentlyselected from H, benzyloxy, benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄alkoxy, and NO₂; the B ring is pyrrolidinyl, tetrahydroisoquinolinyl,piperidinyl, pyrrolidinonyl, thiazolidinyl, pyrrolyl, pyrazolyl,dihydroquinoxalinonyl, pyridinonyl, wherein each is optionallysubstituted with 1, 2, 3, or 4 groups that are independently alkyl,alkoxy, benzyl, benzyloxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH;Q is H, phenyl, indolizinyl, benzofuranyl, indolyl, isoindolyl,quinolinyl, -benzofuranyl-CH₂-phenyl, wherein the aforementioned cyclicgroups are optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,CF₃, OCF₃, NR₆R₇, or phenyl; wherein R₆ and R₇ are independently H,C₁-C₆ alkyl, benzyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl, or—SO₂-phenyl, wherein the phenyl groups are optionally substituted with1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ orOCF₃.
 9. A compound according to claim 8, wherein Y is a bond or—(C₁-C₄) alkyl-.
 10. A compound according to claim 8, wherein Y isselected from —NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄) alkyl C(O)—(C₁-C₄)alkyl-, —(C₁-C₄) alkyl- wherein the alkyl is optionally substituted withphenyl, or —NHC(O)—.
 11. A compound according to claim 1, of the formula

wherein R₁ is H, C₁-C₄ alkyl, benzyl or allyl; the B ring is indolyl,benzimidazolyl, quinolinyl, pyrrolyl, pyrazolyl, pyrimidinyl, orpyridinyl, wherein each is optionally substituted with 1, 2, 3, or 4groups that are independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl,phenyl (C₁-C₄) alkoxy (benzyloxy), halogen, C₁-C₆ alkoxycarbonyl,phenyl, OH.
 12. A compound according to claim 11, wherein Q is H,phenyl, -phenyl-benzyl, -phenyl-pyridyl, -phenyl-benzofuranyl,-phenyl-C₁-C₄ alkyl-benzofuranyl, -phenyl-piperidinyl,-phenyl-pyrrolidinyl, indolizinyl, benzofuranyl, indolyl, isoindolyl,quinolinyl, -benzofuranyl-C₁-C₄ alkyl-phenyl, -pyridyl-C₁-C₄alkyl-phenyl, -piperidinyl, pyrrolidinyl, or indolinyl, wherein theaforementioned cyclic groups are optionally substituted with 1, 2, 3, 4,or 5 groups that are independently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NR₆R₇, orphenyl; wherein R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₄) alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl,(C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₄) alkoxycarbonyl, pyridylcarbonyl, or—SO₂-phenyl, wherein the cyclic groups are optionally substituted with1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄haloalkyl or C₁-C₄ haloalkoxy.
 13. A compound according to claim 12,wherein R₁ is H, or C₁-C₄ alkyl; R₂ is benzyloxy, phenyl, phenyl C₁-C₄alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —SO₂-phenyl,(C₁-C₄) hydroxyalkyl or OH, wherein the aryl group is optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, or NO₂;and R₂₀, and R₂₁ are independently selected from H, benzyloxy, benzyl,halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, and NO₂.
 14. A compoundaccording to claim 13, wherein the B ring is indolyl, benzimidazolyl, orpyridinyl, wherein each is optionally substituted with 1, 2, 3, or 4groups that are independently alkyl, alkoxy, phenyl (C₁-C₄) alkyl,phenyl (C₁-C₄) alkoxy (benzyloxy), halogen, C₁-C₆ alkoxycarbonyl,phenyl, OH; and Y is selected from a bond, —(C₁-C₄) alkyl-,—NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄) alkylC(O)—(C₁-C₄) alkyl-, —(C₁-C₄)alkyl- wherein the alkyl is optionally substituted with phenyl, or—NHC(O)—.
 15. A compound according to claim 1, wherein L₃ is a bond, or—C₁-C₄ alkyl-, the A-ring is benzofuranyl, indolyl, isoindolyl,dibenzofuranyl, or thiazolyl, each of which is optionally substitutedwith 1, 2, or 3 groups that are independently, halogen, C₁-C₆ alkyl,C₁-C₄ alkoxy, haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆) alkyl (C₁-C₆) alkyl; Q is phenyl, indolizinyl, benzofuranyl,indolyl, isoindolyl, quinolinyl, -benzofuranyl-C₁-C₄ alkyl-phenyl,wherein the aforementioned cyclic groups are optionally substituted with1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkoxycarbonyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,NR₆R₇, or phenyl; wherein R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₄)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl,(C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₄) alkoxycarbonyl, or —SO₂-phenyl,wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂,OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄ haloalkyl orC₁-C₄ haloalkoxy.
 16. A compound according to claim 15, wherein R₂ isbenzyloxy, phenyl, phenyl C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆alkyl, C₁-C₆ alkoxy, —SO₂-phenyl, (C₁-C₄) hydroxyalkyl or OH, whereinthe aryl group is optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, or NO₂; the B ring is indolyl,benzimidazolyl, pyridinyl, pyrrolidinyl, pyridinonyl, quinoxalinonyl,pyrrolyl, pyrazolyl benzimidazolyl, quinoxalinyl, wherein each isoptionally substituted with 1, 2, 3, or 4 groups that are independentlyalkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl (C₁-C₄) alkoxy (benzyloxy),halogen, C₁-C₆ alkoxycarbonyl, phenyl, or OH; R₂₀, and R₂₁ areindependently selected from H, benzyloxy, benzyl, halogen, C₁-C₄ alkyl,OH, C₁-C₄ alkoxy, and NO₂, and R₂₂ and R₂₃ are both H.
 17. A compoundaccording to claim 16, wherein L₃ is a bond, or —C₁-C₄ alkyl-, theA-ring is benzofuranyl, indolyl, isoindolyl, dibenzofuranyl, thiazolyl,each of which is optionally substituted with 1, 2, or 3 groups that areindependently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, haloalkyl,haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl (C₁-C₆) alkyl; Qis phenyl, indolizinyl, benzofuranyl, indolyl, -benzofuranyl-C₁-C₄alkyl-phenyl, wherein the aforementioned cyclic groups are optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₂ haloalkyl,C₁-C₂ haloalkoxy, NR₆R₇, or phenyl; wherein R₆ and R₇ are independentlyH, C₁-C₆ alkyl, benzyl, C₂-C₆ alkanoyl, phenyl(C₁-C₂)alkanoyl, or—SO₂-phenyl, wherein the phenyl groups are optionally substituted with1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃, orOCF₃; Z is absent or phenyl optionally substituted with 1, 2, 3, or 4groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, orhydroxy; R₁ is H or C₁-C₆ alkyl; R₂ is benzyloxy, phenyl, phenyl C₁-C₄alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —SO₂-phenyl,(C₁-C₄) hydroxyalkyl or OH, wherein the phenyl group is optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, or NO₂; the B ring is indolyl,benzimidazolyl, pyridinyl, pyrrolidinyl, pyridinonyl, quinoxalinonyl,pyrazolyl, pyrrolyl, benzimidazolyl, quinoxalinyl, wherein each isoptionally substituted with 1, 2, 3, or 4 groups that are independentlyalkyl, alkoxy, phenyl (C₁-C₄) alkyl, phenyl (C₁-C₄) alkoxy, halogen,C₁-C₆ alkoxycarbonyl, phenyl, or OH; R₂₀, and R₂₁ are independentlyselected from H, benzyloxy, benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄alkoxy, and NO₂, and R₂₂ and R₂₃ are both H.
 18. A method of treatingtype 1 or type 2 diabetes comprising administering a pharmaceuticallyacceptable amount of a compound of claim 1 to a patient in need thereof.19. A pharmaceutical composition comprising a compound according toclaim 1 and at least one pharmaceutically acceptable solvent, carrier,excipient or adjuvant.
 20. A compound according to claim 1 which is1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4-(benzyloxy)proline;4-(benzyloxy)-1-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}proline;1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}proline;4-(benzyloxy)-1-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)proline;1-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)proline;2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid;1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}piperidine-2-carboxylicacid;1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}piperidine-3-carboxylicacid; 1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}proline;(2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)aceticacid;(1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}pyrrolidin-2-yl)aceticacid;1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-3-phenylproline;(4R)-1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-4-(benzyloxy)-L-proline;{1-benzyl-5-[4-(1H-indol-1-yl)phenyl]-1H-indol-3-yl}acetic acid;1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-5-oxoproline;[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1-(tert-butoxycarbonyl)-1H-indol-3-yl]aceticacid;{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1-[(4-methyl-3-nitrophenyl)sulfonyl]-1H-indol-3-yl}aceticacid;3-{[5-{4-[(2-butyl-1-benzofuran-3-yl)methyl]phenyl}-2-(3-phenylpropoxy)pyridin-3-yl]amino}-3-oxopropanoicacid;[5-[4-(1H-indol-1-yl)phenyl]-1-(2-naphthylmethyl)-1H-indol-3-yl]aceticacid;(4R)-2-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-1,3-thiazolidine-4-carboxylicacid;(4R)-2-[4′-(1H-indol-1-yl)biphenyl-4-yl]-1,3-thiazolidine-4-carboxylicacid;1-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-4-hydroxyproline;{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}aceticacid;{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}aceticacid;3-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}propanoicacid;4-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}butanoicacid;4-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}butanoicacid;4-[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-(2-phenylethyl)-1H-benzimidazol-1-yl]butanoicacid;4-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}butanoicacid;3-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}propanoicacid;3-[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-(2-phenylethyl)-1H-benzimidazol-1-yl]propanoicacid;{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}aceticacid;3-{1-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-2-yl}propanoicacid;{1-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-2-yl}aceticacid;2-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}-3-phenylpropanoicacid;2-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-methyl-1H-benzimidazol-1-yl}-3-phenylpropanoicacid;2-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}-3-phenylpropanoicacid;[2-benzyl-7-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]aceticacid; methyl1-{[4-({[4-(4-chlorophenyl)-5-(4-ethylphenyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl]sulfonyl}prolinate;{3-[4-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl]-1-benzofuran-2-yl}(phenyl)aceticacid4-(benzyloxy)-1-{[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]carbonyl}-L-proline{5-[4-(1H-indol-1-yl)phenyl]-1-[(4-methyl-3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-indol-3-yl}aceticacid; {5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-indol-3-yl}aceticacid;[6-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl]aceticacid; [4-(4-dibenzo[b,d]thien-4-ylphenyl)piperazin-1-yl](phenyl)aceticacid;({4′-[10-(ethoxycarbonyl)pyrido[1,2-a]indol-3-yl]biphenyl-4-yl}oxy)(phenyl)aceticacid;N-[5-[4-(2-Butyl-benzofuran-3-ylmethyl)-phenyl]-2-oxo-1-(3-phenyl-propyl)-1,2-dihydro-pyridin-3-yl]-malonamicacid;N-[1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamicacid;[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-aceticacid;[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-aceticacid;1-{[4-({[4-(4-chlorophenyl)-5-(4-ethylphenyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl]sulfonyl}proline;{[1-benzyl-5-(4-dibenzo[b,d]furan-4-ylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}(oxo)aceticacid;4-{5-Chloro-1-[4-(dibenzofuran-4-ylamino)-benzyl]-1H-indol-3-yl}-4-oxo-butyricacid;4-{5-Chloro-1-[4-(2-methoxy-dibenzofuran-3-ylamino)-benzyl]-1H-indol-3-yl}-4-oxo-butyricacid;4-[5-Chloro-1-(4-thianthren-1-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyricacid;4-[5-Chloro-1-(4-dibenzofuran-4-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyricacid;4-[5-Chloro-1-(4-dibenzothiophen-4-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyricacid;4-{5-Chloro-1-[2-oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-1H-indol-3-yl}-4-oxo-butyricacid;4-{5-Chloro-1-[2-(5-chloro-3-methyl-benzo[b]thiophen-2-yl)-2-oxo-ethyl]-1H-indol-3-yl}-4-oxo-butyricacid; and pharmaceutically acceptable salts thereof.
 21. A compound ofthe formula

wherein R₁ is H, C₁-C₆ alkyl, or phenyl(C₁-C₆)alkyl; L is a bond, —SO₂—,—C(O)—, or —(C₁-C₄) alkyl-; L₂ is a bond, C₁-C₂ alkylene, —NR₈C(O)—, or—C(O)NR₈—, where R₈ is H or C₁-C₆ alkyl; R₂ is phenyl C₁-C₄ alkoxy,phenyl, naphthyl, phenyl C₁-C₄ alkyl, naphthyl C₁-C₄ alkyl, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, —(C₁-C₄) alkyl-C(O)NH₂,—(C₁-C₄) alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄)alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄)alkyl, —SO₂-phenyl, —SO₂-naphthyl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄)alkyl-piperidinyl, —(C₁-C₄) alkyl-pyrrolidinyl, —(C₁-C₄)alkyl-morpholinyl, or OH, wherein the piperidinyl, pyrrolidinyl andmorpholinyl rings are optionally substituted with 1, 2, 3, or 4 groupsthat are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or—SO₂—(C₁-C₄) alkyl; wherein the phenyl and naphthyl groups areoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or NO₂; wherein b is 0, 1, or 2; A is phenyl, benzofuranyl,or dibenzofuranyl, each of which is optionally substituted with 1, 2, 3,4, or 5 groups that are independently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl,C₁-C₆ alkoxy, hydroxy, nitro, halogen, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy, NR₆R₇, or phenyl; wherein each R₆ and R₇ is independently H,C₁-C₆ alkyl, phenyl(C₁-C₄)alkyl, C₂-C₆ alkanoyl, phenyl(C₁-C₄)alkanoyl,(C₁-C₆)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl, pyridylcarbonyl, or—SO₂-phenyl, wherein the cyclic groups are optionally substituted with1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄haloalkyl or C₁-C₄ haloalkoxy; R₂₀ and R₂₁ are independently selectedfrom H, benzyloxy, benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂,NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl, orN(C₁-C₄)alkyl-phenyl, wherein the phenyl group is optionally substitutedwith 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy; the Bring is pyrrolidinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl,pyrrolidinonyl, pyrazolyl, dihydropyrazolyl, thiazolidinyl,dihydroquinoxalinonyl, pyridinonyl, or dihydroisoquinolinyl, whereineach is optionally substituted with 1, 2, 3, or 4 groups that areindependently alkyl, alkoxy, phenyl (C₁-C₄) alkyl (benzyl), phenyl(C₁-C₄) alkoxy (benzyloxy), halogen, C₁-C₆ alkoxycarbonyl, phenyl, orOH; and Y is a bond, —(C₁-C₄) alkyl- optionally substituted with phenyl,—NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄) alkylC(O)—(C₁-C₄) alkyl-, or —NHC(O)—.22. A compound according to claim 21, wherein L is a bond or —(C₁-C₄)alkyl-.
 23. A compound according to claim 22, wherein L₂ is a bond ormethylene.
 24. A compound according to claim 23, wherein R₁ is H orC₁-C₄ alkyl; and R₂ is benzyloxy, phenethyloxy, phenyl, phenyl C₁-C₄alkyl, —CH₂-naphthyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,—(C₁-C₄) alkyl-S(O)₂—(C₁-C₄) alkyl, —SO₂-phenyl, (C₁-C₄) hydroxyalkyl,—(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄) alkyl-pyrrolidinyl, —(C₁-C₄)alkyl-morpholinyl, or OH, wherein the piperidinyl, pyrrolidinyl andmorpholinyl groups are optionally substituted with a total of 1, 2, or 3groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or—SO₂—(C₁-C₄) alkyl; wherein the phenyl and naphthyl groups areoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or NO₂.
 25. A compound according to claim 24 wherein R₁ isH.
 26. A compound of claim 25, wherein R₂₀ and R₂₁ are independentlyselected from H, benzyloxy, benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.
 27. Acompound according to claim 24, wherein R₂ is benzyloxy, phenyl, phenylC₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,—SO₂-phenyl, (C₁-C₄) hydroxyalkyl or OH, wherein the phenyl groups areoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or NO₂; and R₂₀ and R₂₁ are independently selected from H,benzyloxy, benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, and NO₂. 28.A compound according to claim 27, wherein the B ring is benzimidazolyl,pyrazolyl, dihydropyrazolyl, or pyridinonyl, wherein each is optionallysubstituted with 1, 2, or 3 groups that are independently alkyl, alkoxy,phenyl (C₁-C₄) alkyl, benzyloxy, halogen, C₁-C₆ alkoxycarbonyl, phenyl,or OH; and Y is selected from a bond, —NHC(O)—(C₁-C₄) alkyl-, —N(C₁-C₄)alkylC(O)—(C₁-C₄) alkyl-, or —NHC(O)—.
 29. A compound according to claim21 or 28, wherein the A-ring is benzofuranyl or dibenzofuranyl, each ofwhich is optionally substituted with 1 or 2 groups that areindependently, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, haloalkyl,haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆) alkyl. 30.A compound according to claim 29, wherein R₂ is benzyloxy, phenyl,phenyl C₁-C₄ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,—SO₂-phenyl, (C₁-C₄) hydroxyalkyl or OH, wherein the aryl group isoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, or NO₂. R₂₀ and R₂₁ are independently selected from H,benzyloxy, benzyl, halogen, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, and NO₂. 31.A compound according to claim 21 of the formula:

wherein R₁ is H or C₁-C₆ alkyl; L is a bond or C₁-C₂ alkylene; L₂ is abond or —CH₂—; A represents

where R₁₀ and R₁₀, independently represent hydrogen, halogen, C₁-C₆alkyl, C₁-C₄ alkoxy, haloalkyl, haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl; and Y is a bond, —NHC(O)— or —NHC(O) (C₁-C₂)alkyl-.
 32. A compound according to claim 31, wherein R₁₀ is C₁-C₆alkyl.
 33. A compound according to claim 32 wherein the B ring is1-dihydropyrazolyl, 1-pyridinonyl or 1-pyrazolyl, each of which isoptionally substituted with 1 or 2 groups that are independently alkyl,alkoxy, benzyl, phenethyl, benzyloxy, halogen, C₁-C₆ alkoxycarbonyl,phenyl, or OH.
 34. A compound according to claim 33 wherein L is a bond.35. A compound according to claim 34 wherein Y is a bond.
 36. A compoundaccording to claim 34, wherein Y is —NHC(O)—.
 37. A compound accordingto claim 34, wherein Y is —NHC(O) (C₁-C₂)alkyl-.
 38. A compoundaccording to claim 31, wherein R₁₀ is not hydrogen and R₁₀, is hydrogen.